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WORKS  OF  DR.  MARTIN  H.  FISCHER 

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The  Physiology  of  Alimentation. 

Large  i2mo,  viii  +  348  pages,  30  figures,  cloth,  $2.00  net. 

(Edema.    A  Study  of  the  Physiology  and  the  Pathology 
of  Water  Absorption  by  the  Living  Organism. 

8vo,   209  pages,   51  figures,   including  full-page  plates,  cloth, 
$2.00  net. 

Nephritis.      An  Experimental  and  Critical  Study  of  its 
Nature,  Cause,  and  the  Principles  q,f  its  Relief. 

Large  i2mo,  ix  +  203   pages,  31  figiires,  including  a  colored 
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TRANSLATION 

Physical  Chemistry  in  the  Service  of  Medicine. 

Seven  addresses  by  Dr.  Wolfgang  Pauli,  Professor  in  the 
University  of  Vienna.  Authorized  translation  by  Dr.  Martin 
H.  Fischer.     i2mo,  k  +  156  pages,  cloth,  $1.25  net. 


NEPHRITIS 

AN    EXPERIMENTAL  AND    CRITICAL   STUDY 

OF   ITS    NATURE,   CAUSE   AND    THE 

PRINCIPLES    OF    ITS    RELIEF 


BY 

DR.    MARTIN    H.    FISCHER 

Bichberg  Professor  of  Physiology  in  the   University  of  Cincinnati 


^> 


THE    191 1    CARTWRIGHT    PRIZE    ESSAY 

OF   THE 

ASSOCIATION  OF  THE  ALUMNI  OF  THE  COLLEGE  OF 
PHYSICIANS  AND   SURGEONS,  MEDICAL  DEPART- 
MENT OF  COLUMBIA  UNIVERSITY,  NEW  YORK 


FIRST   EDITION- 
FIRST  THOUSAND 


NEW   YORK 
JOHN    WILEY    &    SONS 

London:  CHAPMAN  &  HALL,  Limited 
1912 


Copyright,  191  i, 

BY 

MARTIN    H.    FISCHER 


Stanbopc  Press 

H.CILSON     COMPANY 
BOSTON.      U.S.A. 


biomedical 
Library 


TO 

C.  R.  F. 


OUSiC'\-)<L 


PREFACE. 

The  following  pages  constitute  a  continuation  of  the  ex- 
perimental studies  in  clinical  physiology  which  were  pub- 
lished last  year  under  the  title  (Edema}  The  second  half 
of  the  present  volume  brings  a  detailed  account  of  observa- 
tions touched  upon  only  incidentally  there,  which  show 
how  some  of  the  severest  grades  of  nephritis  which  are 
generally  held  to  present  considerable  difficulties  in  treat- 
ment may  be  easily  relieved.  The  methods  adopted  to 
accomplish  this  purpose  are  in  no  small  way  different  from 
certain  forms  of  practice  common  to-day.  Any  hope  that 
they  may  find  general  acceptance  can  therefore  be  enter- 
tained only  if  the  principles  upon  which  the  suggested 
therapy  is  based  have  been  correctly  enunciated.  What  to 
my  mind  these  are  constitutes  the  first  half  of  the  volume. 

It  is  impossible  to  mention  by  name  all  those  of  my 
friends  and  colleagues  who  with  suggestion  and  criticism 
have  helped  along  the  days'  work.  Mr.  Thomas  Kelly 
and  Dr.  William  H.  Strietmann  have  been  enthusiastic  and 
willing  coworkers;  Prof.  Lauder  W.  Jones  helped  me  with 
his  store  of  chemical  knowledge;  Mr.  Alfred  Brodbeck  took 
interest  in  the  observations  made  on  athletes;  Dr.  Charles 
Goosman  gave  of  his  time  and  skill  to  prepare  the  photo- 
micrographs ;  Mr.  Charles  Hecker  and  Mr.  Peter  Scherrer  of 
theirs  to  make  the  remaining  photographs;  Mr.  Paul  M. 
Stewart  arduously  deciphered  the  manuscript.  Very  sincere 
thanks  are  tendered  all  of  them. 

Martin  H.  Fischer. 

University  of  Cincinnati, 
June,  19 II. 

^  CEdema.  A  Study  of  the  Physiology  and  the  Pathology  of  Water 
Absorption  by  the  Living  Organism.  New  York,  19 10.  John  Wiley  and 
Sons,  Publishers. 

vii 


TABLE   OF   CONTENTS. 

Introductory  Paragraph. 

I.  The  Albuminuria:  Page 

1.  Introduction 2 

2.  The  Physicochemical  Structure  of  the  Kidney 5 

3.  Introductory  Remarks  on  Colloids  and  the  Colloidal  State  7 

4.  Observations  on  the  "  Solution "  of  Colloidal  (Protein) 

Gels 9 

5.  Albuminuria  as  a  Phenomenon  Identical  with  the  "  Solu- 

tion "  of  a  Protein  Gel 19 

1.  Evidence  Indicating  that  an  Abnormal  Production 
or  Accumulation  of  Acid  Occurs  in  Every  Case  of 
Albuminuria 21 

2.  Any  Means  which  Leads  to  an  Increased  Production 
or  Accumulation  of  Acids  in  the  Kidney  is  a  Means  of 
Producing  Albuminuria 25 

II.  The  Morphological  Changes  in  the  Kidney: 

1.  Introduction 56 

2.  The  Relation  Morphologically  of  the  So-called  Chronic 

Interstitial  Nephritis  to  the  Parenchymatous  Types.        58 

3.  The  Changes  in  the  Size  and  in  the  Color  of  the  Kidney 

in  Nephritis  (Cloudy  Swelling) 61 

4.  The  Bleeding  into  and  from  the  Kidney  in  Nephritis 

(Haemorrhage  by  Diapedesis) 78 

5.  On  the  Origin  and  the  Different  Types  of  Tube  Casts ...       84 
HI.  The  Disturbances  in  Secretion  in    Nephritis: 

1.  General  Considerations 93 

2.  Further  Remarks  on  the  Relation  of  Chronic  Interstitial 

Nephritis  to  the  Parenchymatous  Types 94 

3.  The  Secretion  of  Water  by  the  Nephritic  Kidney 102 

4.  The  Changes  in  the  Secretion  of  Dissolved  Substances  by 

the  Nephritic  Kidney 113 

IV.   On  the  Treatment  of  Nephritis: 

1.  Some  General  Considerations 125 

2.  Water  Consumption  in  Nephritis 129 

3.  The  Role  of  Salts  in  the  Rehef  of  Nephritis 134 

4.  On  the  Treatment  of  (Edema 183 

Concluding  Paragraph. 

ix 


NEPHRITIS 


AN    EXPERIMENTAL   AND    CRITICAL    STUDY 

OF   ITS    NATURE,    CAUSE    AND    THE 

PRINCIPLES    OF    ITS    RELIEF. 


That  which  we  as  clinicians  have  come  to  regard  as  a 
clinical  entity,  and  call  nephritis,  represents  in  reality  an 
aggregate  of  a  number  of  conditions  each  of  which  must  be 
treated  separately  if  we  would  come  to  a  satisfactory  un- 
derstanding of  that  which  is  included  under  the  clinical 
term.  At  least  silently,  the  necessity  for  such  a  division  of 
the  subject  has,  as  a  matter  of  fact,  long  been  recognized, 
for  have  we  not  largely  given  up  the  discussion  of  nephritis 
and  taken  up  more  and  more  albuminuria,  anuria,  oedema, 
chloride  retention  —  all  of  them  parts  of  nephritis?  Yet 
the  persistence  of  the  term  nephritis  in  spite  of  our  daily 
efforts  in  medicine  to  become  scientifically  more  precise 
seems  to  be  not  without  reason;  it  is  the  one  term  by 
which  we  are  enabled  to  express  the  fact  that  the  albumi- 
nuria, the  anuria,  etc.,  nearly  always  appear  as  associated 
phenomena.  But  from  such  a  constancy  in  association  we 
are  enabled  to  draw  an  important  conclusion  —  they  must 
all  have  a  common  cause.  The  following  pages  attempt  to 
show  what  this  is;  they  try,  in  other  words,  to  estabHsh 
what  is  the  underlying  "  cause  "  of  nephritis. 

The  term  nephritis  is  used  throughout  this  paper  in  the 
generally  accepted  meaning  of  that  word  as  the  "  non- 
purulent inflammations  of  the  kidney."     As  will  appear 


2  NEPHRITIS 

later,  this  division  from  the  purulent  forms  is  purely  arbi- 
trary but  it  is  adhered  to  because  pathologists  have  made 
this  division,  and  it  possesses  certain  immediate  advantages 
for  ease  in  discussion. 

To  render  our  argument  clear,  we  will  at  once  state  our 
general  conclusion: 

All  the  changes  that  characterize  nephritis  are  due  to  a 
common  cause  —  the  abnormal  production  or  accumulation  0} 
acid  ifi  the  cells  of  the  kidney.  To  the  action  of  this  acid  on 
the  colloidal  structures  that  make  up  the  kidney  are  due  the 
albuminuria,  the  specific  morphological  changes  noted  in  the 
kidneys,  the  associated  production  of  casts,  the  quantitative 
variations  in  the  amount  of  urine  secreted,  the  quantitative 
variations  in  the  amounts  of  dissolved  substances  secreted,  etc. 

The  proof  of  this  contention  and  the  discussion  of  how 
this  one  factor  of  acid  production,  or  accumulation,  in  the 
kidney  operates  to  produce  the  various  changes  character- 
istic of  nephritis  appears  from  the  experimental  findings 
that  follow.  We  will  pass  at  once  to  a  seriatim  analysis  of 
the  chief  objective  signs  that  as  clinicians  we  have  come  to 
regard  as  characteristic  of  nephritis. 


I.   THE  ALBUMINURIA. 

I.   Introduction. 

The  urine  of  man  or  of  the  various  animals  that  serve  us 
for  experimental  purposes  does  not  under  normal  circum- 
stances contain  albumin  in  an  amount  that  betrays  itself 
when  any  of  our  ordinary  laboratory  tests  are  applied  to 
it.  By  special  methods  it  is  possible  to  show  that  even 
such  normal  urine  contains  faint  traces  of  albumin,  but  it 
is  generally  held  that  this  is  of  no  pathological  significance 
and  has  behind  it  a  no  more  serious  cause  (it  is  thought) 


NEPHRITIS  3 

than  the  shedding  and  destruction  of  a  few  cells  from  the 
tract  through  which  the  urine  has  to  pass  from  the  urinif- 
erous  tubules  into  the  outer  world.  An  albuminuria,  as 
we  shall  use  the  term,  will  therefore  have  a  meaning  only 
as  applied  to  the  presence  of  albumin  beyond  this  normal 
amount,  and  we  ought  to  add  of  renal  origin  and  not  from 
somewhere  below  this  organ.  Neither  are  we  concerned 
with  a  discussion  of  those  albuminurias  which  are  the  con- 
sequence of  the  grosser  destructive  lesions  of  the  kidney  as 
in  abscess.  What  demands  an  answer  is  the  cause  of  those 
albuminurias  in  which  no  such  gross  lesions  are  apparent, 
where  a  kidney,  roughly  speaking,  is  rather  normal  in  ap- 
pearance, and  still  is  the  source  maybe  of  large  quantities 
of  albumin. 

Our  current  hypotheses  regarding  the  cause  of  albumi- 
nuria are  familiar  to  everyone  and  are  notoriously  unsatis- 
factory. It  is  generally  held  that  the  (chief)  albumin  of 
albuminuria  is  serum  albumin,  that  it  is  derived  from  the 
blood,  and  that  it  is  under  normal  circumstances  prevented 
from  going  over  into  the  urine  by  the  kidney  structures 
which  He  between  the  urine  and  the  blood.  Some  twenty 
years  ago  R.  Heidenhain  attempted  to  express  the  whole  sit- 
uation in  satisfactory  physicochemical  terms.  He  pointed 
out  the  colloid  nature  of  the  blood  albumins,  and  called 
to  mind  Thomas  Graham^ s  fundamental  differentiation  be- 
tween the  colloids  which  do  not  diffuse  through  animal 
membranes  and  the  crystalloids  which  do  this  readily.  On 
this  basis  he  maintained  that  the  latter  appeared  in  the 
urine  because  they  could  readily  diffuse  through  the  animal 
membrane  that  separates  the  urine  from  the  blood,  while 
albumin  is  absent  because  this  colloidal  body  cannot  diffuse 
through  such  a  membrane.  We  have  not  since  Heiden- 
hain's  considerations  gotten  beyond  this  view. 

Simple  and  apparently  satisfactory  as  this  explanation  is, 


4  NEPHRITIS 

it  cannot  stand  the  pressure  of  a  little  analysis.  In  ne- 
phritis this  membrane  is  of  course  still  present  and  yet  in 
this  pathological  state  the  albumin  appears  in  the  urine. 
To  meet  this  fact  it  has  been  generally  maintained,  and, 
let  us  add,  without  any  experimental  support  whatsoever, 
that  the  "  permeability  "  of  the  urinary  membrane  for 
albumin  has  been  altered,  so  that  it  now  lets  this  through. 
As  a  matter  of  fact  we  have  not  even  had  offered  us  any 
parallel  from  the  pages  of  physical  chemistry  for  such  a 
change  in  the  permeability  of  any  '^  membrane  "  that  in 
the  laboratory  corresponds  with  such  as  we  might  have  in 
the  body,  nor,  so  far  as  I  know,  has  anyone  attempted  to 
say  just  what  chemical  or  physicochemical  agent  is  re- 
sponsible for  the  changes  in  permeability  postulated  in  the 
case  of  the  kidney. 

A  first  error  in  this  theory  of  albuminuria  (which  repre- 
sents the  epitome  of  our  present  conceptions  regarding  its 
nature)  arises  from  the  fact  that  the  albumin  found  in  the 
urine  is  looked  upon  as  coming  from  the  blood.  Such  a  belief 
has  been  entertained  because  it  has  been  found  that  the 
albumin  present  in  the  urine  shows  a  series  of  reactions 
which  are  identical  with  those  obtained  from  serum  albumin. 
But  this  does  not  yet  prove  that  the  albumin  of  albumi- 
nuria has  come  directly  from  the  blood.  Such  a  conclusion 
overlooks  the  very  important  fact  that  the  albumins  con- 
tained in  the  kidney  itself,  in  other  words  the  albumins 
contained  in  the  secreting  membrane  separating  the  urine 
from  the  blood,  also  show  these  reactions.  None  of  the 
albumin  reactions  used  in  these  tests  are  ''specific."  They 
only  represent  certain  group  reactions  which  colloid  chemis- 
try has  shown  us  to  be  common  to  a  large  number  of  the 
emulsion  colloids  of  animal  origin.  Such  considerations 
carry  with  them  the  important  conclusion  that  the  albumin 
of  albuminuria  need  not  come  from  the  blood  at  all  {except 


NEPHRITIS  5 

indirectly),  it  may  come  from  the  urinary  membrane  itself. 
That,  as  a  matter  of  fact,  it  does  come  from  this  will  appear 
more  distinctly  as  we  proceed.  At  this  point  let  us  express 
our  conviction  that  albuminuria  results  lihaievcr  conditions 
are  ofcrcd  in  the  body  li'hich  permit  tJie  solid  colloidal 
membrane  that  separates  the  blood  from  tJie  urine  to  go  into 
solution  in  the  urine.  A  chief  reason  why  this  occurs  in 
nephritis  resides  in  the  fact  that  in  this  condition  acids  are 
produced  which  render  the  colloidal  membrane  '* soluble." 
To  make  clear  what  is  meant  by  this  conclusion  the  fol- 
lo-^ing  remarks  on  the  general  structure  of  the  kidney,  and 
the  introduction  of  some  obser\'ations  on  this  question  of 
the  ^'  solubiHty  "  of  colloids  are  necessar}-. 

2.   The  Physicochemical  Structure  of  the  Kidney. 

The  system  that  is  involved  in  the  production  of  urine 
consists  in  the  main  of  three  parts  or  phases  —  the  blood, 
the  urinary  membrane,  and  the  urine. 

The  blood  consists  of  a  liquid  portion  in  which  are  floating 
various  nucleated  and  non-nucleated  cells.  These  cells 
are  fairly  soHd  colloid  structures  that  in  their  general 
properties  are  often  said  to  be  "jellylike,"  a  characteri- 
zation that  really  Jits  them  very  well,  for  in  their  general 
biological  behavior  they  are  not  unUke  a  stiffened  gelatine, 
for  example.  But  the  liquid  portion  of  the  blood  is  also 
essentially  colloid  in  character,  only  the  colloids  here  are  in 
a  fluid  state.  It  corresponds,  say,  with  a  ''  solution  "  of 
gelatine  or  of  albumin  or  globulin.  Present  in  both  the 
Hquid  and  the  solid  portions  of  the  blood  are  normally  a 
number  of  salts  and  various  norielectrolytes  which  play  an 
important  part  in  maintaining  the  normal  state  of  the 
colloids  that  are  found  here.  For  the  sake  of  bre\aty  we 
\^ill  ordinarily  in  tliis  paper  refer  to  the  whole  blood  as  a 
single  phase,  and  so  as  one  of  the  phases  making  up  the 


6  NEPHRITIS 

urinar>'  secretor>'  system.  We  need  not  especially  empha- 
size the  fact  that  taken  strictly  this  is  not  correct;  there 
really  exist  several  phases  within  the  blood  itself. 

Under  the  urinary  membrane  we  will  include  all  the 
structures  that  lie  between  the  blood  on  the  one  side  and 
the  urine  on  the  other.  The  urinary  membrane  as  we  will 
use  the  term  is  made  up  of  all  the  different  cells  that  are 
found  between  the  blood  on  the  one  side  and  the  urine  on 
the  other,  together  with  their  various  intercellular  sub- 
stances. The  whole  constitutes  a  fairly  firm  structure  to 
which  we  may  again  apply  the  term  "  jellylike."  In  the 
terms  of  physical  chemistr}^  this  membrane  consists  of  a 
mixture  of  various  emulsion  colloids  in  the  solid  or  gel 
state.  We  find  present  here  also,  as  in  all  the  body  tis- 
sues, various  electrolytes  and  nonelectrolytes.  This  mem- 
brane has  not  the  same  composition  ever}'where.  Not 
only  does  histological  evidence  show  a  striking  difference 
in  the  character  of  the  cells  that  make  up  the  different 
parts  of  the  urinajy^  membrane  (different  cell  structure  in 
the  glomeruH,  convoluted  and  straight  tubules,  etc.)  but  so 
does  physiological  evidence  (absorption  of  dyes).  So  this 
membrane  also  is  itself  composed  of  several  phases,  but  un- 
less specially  noted  we  will  simply  refer  to  the  whole  as  the 
second  phase  of  our  secretor}^  system. 

The  third  phase  of  our  secretory  system,  is  formed  by  the 
urine.  As  is  well  known  this  is,  under  normal  conditions, 
an  aqueous  solution  of  various  cr}'stalloids,  —  electrolytes, 
and  nonelectrolytes.  Colloidal  material  is  present  in  only 
ver>'  small  amount  and  consists  of  that  trace  of  albumin  al- 
ready referred  to  that  is  found  in  normal  urine,  together 
with  some  mucin,  etc.,  derived  from  the  urinary^  tract. 
When  the  urine  becomes  albuminous,  as  in  nephritis,  this 
colloid  content  rises.  As  we  have  said,  this  is  because 
in  albuminuria  tJte  albumin  of  the  urinary  membrane  goes  into 


NEPHRITIS  7 

"  solution  "  in  the  urine;  the  solid  colloidal  urinary  mem- 
brane (a  gel)  becomes  a  sol.  To  indicate  what  is  meant  by 
this  and  to  show  what  are  the  conditions  that  make  certain 
soHd  colloids  of  the  type  that  we  know  compose  the  urinary 
membrane  go  into  "  solution  "  we  will  detail  some  obser- 
vations on  the  subject. 

3.  Introductory  Remarks  on  Colloids  and  the  Colloidal 

State. 

As  is  familiar  to  everyone  since  the  classical  studies  of 
Thomas  Graham  on  diffusion,  different  chemical  substances 
differ  greatly  in  the  rate  with  which  they  diffuse  through 
solvents  of  various  kinds.  While  such  crystalHne  bodies 
as  the  sugars,  the  salts,  and  urea  diffuse  rapidly,  the  amor- 
phous bodies  represented  by  glue,  starches,  and  various 
albumins  do  so  only  very  slowly.  While  no  absolutely 
sharp  dividing  line  may  be  drawn  between  these  two  groups, 
the  behavior  of  the  t}^ical  members  of  the  former  is  so 
decidedly  different  from  the  behavior  of  the  second  that 
there  is  ample  justice  in  calling  the  first  crystalloids  and 
the  second  colloids. 

Of  the  various  substances  that  may  be  found  classed 
under  the  heading  colloids  it  is  again  possible  to  distinguish 
between  two  great  groups.  One  of  these  consists  of  those 
colloids  that  are  viscous,  gelatinizing  bodies  which  cannot 
be  readily  precipitated  by  salts,  while  another  is  made  up 
of  the  nonviscous,  nongelatinizing  ones  that  are  easily 
precipitated  by  salts  {A.  A.  Noyes^).  Typical  examples  of 
the  former  class  are  found  in  gelatine  and  various  albumins, 
of  the  latter  in  the  colloidal  solutions  of  various  metals  and 
certain  dyes.  The  essential  difference  between  the  two 
resides  in  the  relation  which  the  colloid  bears  to  the  solvent 
in  which  it  finds  itself.  When  these  two  classes  of  colloids 
*  A.  A.  iVo;yej;  Journal  of  the  American  Chemical  Society,  27,  85  (ipc^). 


8  NEPHRITIS 

arc  obtained  in  a  solid  form  it  is  found  that  the  former  con- 
tains much  of  the  solvent  while  the  latter  holds  little  or 
none.  For  this  reason  the  former  are  also  known  as  lyophilic 
or,  if  water  is  the  solvent,  hydrophilic,  the  latter  as  lyophobic 
or  hydrophobic  colloids  (/.  Perrin^  and  H.  Freundlich-). 
But  the  terms  most  employed  take  cognizance  of  the  fact 
that  the  separation  of  the  solvent  from  the  colloid  is  diffi- 
cult to  obtain  in  the  one  case  because  the  colloid  present 
in  it  is  itself  a  Hquid  while  this  separation  is  easier  when 
the  colloid  is  a  solid.  For  this  reason  the  lyophilic  colloids 
are  identical  with  the  emulsion  colloids  (or  emulsoids),  the 
lyophobic  with  the  suspension  colloids  (or  suspensoids)  of 
Wolfgang  Ostwald} 

Of  these  two  groups  of  colloids  our  immediate  problem  is 
most  concerned  with  the  emulsion  colloids,  for  it  is  of  a 
mixture  of  these  that  the  urinary  membrane  is  composed. 

The  emulsion  colloids  are  capable  of  existing  in  two 
fairly  well  defined  states :  in  a  solid  or  gel  state  and  in  a  liquid 
or  sol  state.  A  familiar  example  of  this  fact  is  found  in  ordi- 
nary gelatine.  Under  certain  conditions  this  appears  in  the 
form  of  a  stiff  jelly,  under  others  as  a  "  solution."  In  the 
same  way  fibrin  represents  the  gel  form  of  the  sol  fibrinogen, 
paracasein  (casein)  the  gel  of  casein  (caseinogen) ,  ordinary 
soft  rubber  the  gel  of  a  "  dissolved  "  rubber,  etc. 

It  is  generally  recognized  that  in  the  case  of  the  emulsion 
colloids  a  rather  close  relationship  exists  between  the  gel 
state  in  which  the  colloid  is  ''  swelled  "  and  the  sol  state  of 
this  same  colloid  in  which  it  is  "dissolved,"  and  yet  the  tran- 
sition from  the  one  state  into  the  other  is  not  a  perfectly 
smooth  affair.     We  need  only  call  attention  to  the  fact  that 

*  /.  Pcrrin:  Journal  de  Chimie  Physique,  3,  84  (1905). 

*//.  Freundlich:  Kolloid  Zeitschr.,  3,  80  (1908).  Kapillarchemie,  309, 
Leipzig,  1909. 

^  Wolfgang  Ostwald:  Kolloid  Zeitschr.,  1,  291  and  331  (1907).  Grundriss 
der  KoUoidchemie.    Zweite  Aufl.     Dresden,  191 1. 


NEPHRITIS  9 

ordinary  gelatine,  for  example,  when  thrown  into  cold  water 
merely  swells  up  —  it  enters  the  gel  state.  But  in  this  state 
it  remains,  one  might  almost  say  indefinitely;  to  mere  ap- 
pearance it  does  not  seem  to  go  into  solution  at  all  as  would, 
for  example,  the  crystals  of  any  salt  that  had  thus  been 
thrown  into  the  solvent.  But  if  the  temperature  of  the 
water  is  raised  then  the  gelatine  goes  into  solution  rapidly  — 
it  passes  over  into  the  sol  state.  A  change  in  temperature 
in  this  case  is  necessary  to  accomplish  its  "  solution."  As 
to  our  mind  albuminuria  represents  just  such  a  passage  of 
a  colloid  in  the  gel  state  (the  proteins  of  the  urinary  mem- 
brane) over  into  a  colloid  in  the  sol  state  (the  proteins  con- 
tained in  the  urine  of  the  albuminuric  individual),  let  us 
study  the  conditions  favoring  such  a  transition  in  a  little 
more  detail,  paying  especial  attention  to  a  consideration  of 
the  influence  of  such  changes  in  surroundings  as  we  might 
imagine  could  come  into  play  in  the  cells  of  the  living  ani- 
mal. I  studied  fibrin  and  gelatine  in  this  regard.  The  fol- 
lowing facts  regarding  their  behavior  are  of  importance  in 
the  further  development  of  our  subject. 

4.  Observations  on  the  "  Solution  "  of  Colloidal  (Protein) 

Gels. 

{a)  Fibrin.  —  When  well- washed  fibrin  that  has  been 
thoroughly  dried  and  then  powdered  in  a  mortar  is  thrown 
into  water  it  swells  up  somewhat.  Even  though  the  vessel 
is  thoroughly  shaken  none  of  the  protein  goes  into  solution  in 
the  water.  The  matter  is  easily  tested  by  filtering  the 
water  off  the  fibrin  and  then  treating  the  filtrate  in  any  of 
the  accepted  ways  for  albumin.  One  must  only  be  careful 
in  this  simple  experiment  to  use  a  fine  filter  or  else  not 
powder  the  fibrin  so  thoroughly  that  gross  particles  of  it 
can  pass  through  the  pores  of  an  ordinary  paper  filter.  By 
similar  means  it  can  be  shown  that  the  fibrin  will  not  dis- 


10  NEPHRITIS 

solve  in  any  solution  of  the  ordinary  neutral  salts.  On  the 
other  hand,  if  the  fibrin  is  placed  in  a  solution  of  any  acid 
{or  alkali)  it  not  only  swells  up  more  than  in  water  hut  it  goes 
into  solution.  Within  certain  limits  more  and  more  fibrin 
goes  into  ''  solution  "  with  ever}-  increase  in  the  concentra- 
tion of  the  acid  (or  the  alkali).  But  in  this  matter  there 
seems  to  exist  an  optimum  above  which  the  progressive 
increase  in  **  solution  "  stops  and  gives  way  to  a  fall  in  this 
regard.  The  optimum  point  for  the  "  solution "  of  the 
fibrin  seems,  so  far  as  my  present  experiments  indicate,  to 
coincide  with  the  optimum  found  for  the  "  swelling  "  of 
this  same  substance.  There  is,  moreover,  an  upper  limit 
to  the  total  amount  of  the  fibrin  that  goes  into  solution  in  a 
given  volume  of  the  solvent.  Under  given  conditions  one 
has  quite  as  much  albumin  in  '^  solution  "  after  shaking  a 
mixture  for  two  or  three  hours  as  after  two  or  three  days. 

In  a  given  acid  or  alkali  mixture  the  amount  of  fibrin  that 
will  '^  dissolve ''  is  fnarkedly  decreased  through  the  addition  of 
any  neutral  salt.  With  a  progressive  increase  in  the  con- 
centration of  the  salt  there  is  a  progressive  decrease  in  the 
amount  of  the  fibrin  that  ^'  dissolves."  But  the  character 
of  the  salt  is  not  immaterial.  When  equimolecular  solu- 
tions of  different  salts  are  compared  it  is  found  that  some 
act  more  powerfully  than  others,  but  on  the  basis  of  my 
experiments  as  thus  far  carried  out  it  is  as  yet  unsafe  to 
state  definitely  the  order  in  which  the  various  ions  affect  the 
"  solution  "  of  the  solid  gel.  The  order  seems,  however,  to 
be  identical  with  the  order  in  which  the  ions  affect  the 
swelling  of  fibrin.  Monovalent  ions  are,  as  a  group,  less 
powerful  in  decreasing  the  "  solution  "  of  fibrin  in  an  acid 
or  an  alkali  than  are  bivalent  ions,  and  these  than  trivalent 
ions. 

What  has  been  said  will  be  rendered  clearer  by  intro- 
ducing the  results  of  a  few  typical  experiments.    Figure  i  in- 


NEPHRITIS 


II 


dicates  the  general  way  in  which  these  experiments  were 
performed.  Weighed  amounts  of  powdered  fibrin  were 
placed  in  measured  volumes  of  various  solutions  contained 
in  Erlenmeyer  flasks  which  were  then  placed  in  a  shaking 


Fig.   I. 

machine  and  shaken  for  various  periods  of  time.  At  the 
expiration  of  this  time  the  fibrin  was  allowed  to  settle,  and 
the  supernatant  liquid  was  decanted  off  into  a  filter-lined 
funnel  and  received  into  a  second  flask.  After  stirring  the 
filtrate,  a  measured  volume  was  taken  and  the  amount  of 
albumin  contained  in  it  determined  quantitatively  through 
precipitation  with  phosphotungstic  acid^  and  measurement 
of  the  heights  of  the  precipitate  either  in  the  graduated 
EshacJi  albuminometer  tubes  or  ordinary  test  tubes  of  uni- 
form diameter.  As  the  experiments  are  purely  compara- 
tive in  character  I  have  contented  myself  in  this  paper 
with  simply  photographing  the  results  of  a  few  of  such  ex- 
periments as  have  a  direct  bearing  upon  our  subject. 

^  The  phosphotungstic  acid  reagent  had  the  following  composition: 
Phosphotungstic  acid,  loo  grams. 
Sulphuric  acid  (sp.  gr,  1.84),  100  grams. 
Water  enough  to  make  1000  c.c. 


12 


NEPHRITIS 


Experiment  i.  —  0.5  gram  of  powdered  fibrin  was  shaken  up  for 
5  hours  in  each  of  the  following  solutions: 


I. 

50  c.c. 

0.008  normal  HCl 

2. 

50  c.c. 

0.012  normal  HCl 

3- 

50  c.c. 

0.02    normal  HCl 

4- 

50  c.c. 

0.04    normal  HCl 

5- 

50  c.c. 

0.1      normal  HCl 

6. 

50  c.c. 

H2O. 

The  appearance  of  the  fibrin  in  each  of  .the  flasks  at  the  end  of  this 
time  is  shown  in  Fig.  i.  In  the  first  three  flasks  (i,  2,  3)  there  is  a 
progressive  increase  in  the  swelling  of  the  fibrin  with  the  progressive 
increase  in  the  concentration  of  the  acid.     Beyond  this  point  (flasks 


Fig.  2. 

4  and  5)  there  is  a  decrease  in  the  swelling  in  spite  of  the  further 
increase  in  the  concentration  of  the  aci^.  The  least  amount  of 
swelling  is  noted  in  flask  6  which  contains  water  only.  The  solu- 
tion of  the  fibrin  is  indicated  in  Fig.  2.  From  left  to  right  these  tubes 
correspond  with  the  flasks  of  Fig.  i.  No  precipitate  of  albumin  is 
seen  in  the  tube  on  the  extreme  right,  indicating  that  the  fibrin  did 


NEPHRITIS 


13 


not  go  into  solution  in  the  water  (neutral  reaction).    All  the  remain- 
ing tubes  show  a  precipitate  of  albumin. 

Experiment  2.  —  0.5  gram  of  powdered  fibrin  is  put  into  each  of 
the  following  solutions  and  shaken  for  5  hours : 

1.  10  c.c.  To  normal  HCl  +  40  c.c.  H2O. 

2.  10  c.c.  TO-  normal  HCl  +  40  c.c.  \  molecular  NaCl. 

3.  10  c.c.  tV  normal  HCl  +  40  c.c.  \  molecular  NaCl. 

4.  10  c.c.  To  normal  HCl  +  40  c.c.  \  molecular  NaCl. 

5.  50  c.c.  H2O. 

The  amount  of  albumin  that  went  into  solution  is  indicated  in 
Fig.  3.     No  precipitate  is  seen  in  the  tube  on  the  extreme  right 


Fig.  3. 

(water).  Most  albumin  is  found  in  the  first  tube  (pure  acid  solution;. 
It  is  evident  that  the  presence  of  the  sodium  chloride  reduces  the 
amount  of  the  albumin  that  goes  into  solution.  The  amount  of  this 
reduction  is  the  greater  the  higher  the  concentration  of  the  salt. 

Experiment  3. — 0.5  gram  of  powdered  fibrin  was  placed  in  each  of 
four  flasks  containing  the  following  solutions  and  shaken  for  5  hours: 


14 


XEPHRITIS 


1.  lo  c.c.  i\t  normal  HCl  +  40  c.c.  HjO. 

2.  10  c.c.  15  normal  HCl  +  40  c.c.  |  molecular  Xa2S04. 

3.  10  c.c.  Jo  normal  HCl  -i-  40  c.c.  |  molecular  MgSO*. 

4.  10  c.c.  A  normal  HCl  -|-  40  c.c.  |  molecular  CuSO^. 
After  filtering,  the  amount  of  albumin  dissolved  in  the  supernatant 

liquid  found  above  the  fibrin  in  each  of  the  flasks  was  determined  by 
mixing  20  c.c.  of  filtrate  with  14  c.c.  phosphotungstic  acid.     The  re- 


FiG.  4. 
suit  is  shown  in  Fig.  4.     As  is  readily  apparent,  each  of  the  salts 
markedly  reduced  the  amount  of  albumin  that  was  dissolved. 

Experiment  4.  —  0.5  gram  of  powdered  fibrin  was  introduced 
into  each  of  five  flasks  containing  the  following  solutions  and  shaken 
for  5  hours: 

1.  10  c.c.  ^6  normal  HCl  -f-  40  c.c.  |  molecular  sodium  acetate. 

2.  10  c.c.  15  normal  HCl  -j-  40  c.c.  i  molecular  sodium  nitrate. 

3.  10  c.c.  tV  normal  HCl  +  40  c.c.  |  molecular  sodium  sulphate. 

4.  10  c.c.  ^6  normal  HCl  +  40  c.c.  i  molecular  sodium  citrate. 

5.  10  c.c.  1^0  normal  HCl  +  40  c.c.  H2O. 


NEPHRITIS  15 

The  relative  amounts  of  albumin  found  dissolved  in  each  of  these 
mixtures  at  the  end  of  this  time  are  indicated  in  Fig.  5.     As  is  again 


Fig.  5. 
evident,   most  albumin  was  dissolved  by  the  pure  acid  solution. 
Each  of   the  salts  decreased  through  its  presence  the  amount  thus 

dissolved. 

{h)  Gelatine.  —  What  has  been  said  under  paragraph  (a) 
regarding  tlte  "solution''  of  fibrin  holds  almost  word  for  word 
for  the  "  solution  "  of  gelatine.  The  best  commercial  gela- 
tine shows  some  solubility  in  water.  The  commercial 
product,  as  is  well  known,  has  a  decidedly  acid  reaction. 
WTien,  instead  of  being  placed  in  water,  gelatine  is  dropped 
into  solutions  of  acids  (or  alkalies)  this  solubiHty  of  the 
(commercial)  gelatine  is  greatly  increased.  The  presence  of 
neutral  salts  in  the  acid  (or  alkah)  solution  decreases  the 
amount  of  the  gelatine  that  will  go  into  solution.  As  in 
the  case  of  fibrin  we  note  here  again  a  progressive  decrease 


i6  NEPHRITIS 

in  the  amount  that  "  dissolves  "  with  every  increase  in  the 
concentration  of  the  added  salt.  With  a  given  concentra- 
tion, the  amount  of  such  a  decrease  varies  with  the  salt  em- 
ployed, and  here  again  it  seems  that  monovalent  ions  do 
not  as  a  group  decrease  the  "  solubility  "  of  the  gelatine 
as  much  as  bivalent  ions,  or  these  as  much  as  trivalent 

ions. 

The  following  experiments  will  serve  in  illustration  of 
what  has  been  said. 


Experiment  5.  — 

-  The  fol 

lowing  solutions  we 

I. 

100  c.c. 

H,0. 

2. 

100  c.c. 

o.ooi  normal  HCl. 

3- 

100  c.c. 

0.002  normal  HCl. 

4- 

100  c.c. 

0.005  normal  HCl. 

5- 

100  c.c. 

o.oi    normal  HCl. 

6. 

100  c.c. 

0.015  normal  HCl. 

7- 

100  c.c. 

0.02    normal  HCl. 

8. 

100  c.c. 

0.025  normal  HCl. 

9- 

100  c.c. 

0.035  normal  HCl. 

Five  leaves  of  dry  gelatine,  each  measuring  3I  by  i^  cm.,  weigh- 
ing altogether  0.5  gram,  and  obtained  by  cutting  them  out  of  the 
central  portions  of  the  large  gelatine  leaves  that  are  obtained  com- 
mercially, were  dropped  into  each  of  these  solutions.  From  time  to 
time  the  dishes  containing  the  solutions  with  their  gelatine  leaves 
were  agitated  so  as  to  keep  the  gelatine  from  adhering  to  the  sides, 
and  aid  the  solution  of  the  gelatine.  All  the  vessels  were  treated 
exactly  alike.  The  degree  of  solution  of  the  gelatine  after  28  hours 
in  these  various  solutions  is  indicated  in  Fig.  6.  As  the  photograph 
shows,  least  gelatine  is  dissolved  in  the  pure  water.  With  the  in- 
crease in  the  concentration  of  the  acid  there  is  a  progressive  increase 
in  the  amount  of  dissolved  gelatine,  but  only  up  to  a  certain  point, 
after  which  it  falls  in  spite  of  the  continued  further  increase  in  the 
concentration  of  the  acid. 

Experiment  6.  —  In  the  manner  just  described,  5  leaves  of  dry 
gelatine,  weighing  in  toto  0.5  gram,  and  of  the  same  surface  were 
placed  in  each  of  the  following  solutions: 


NEPHRITIS 


17 


100  c.c.  HoO. 
15  c.c.  To  normal  HCl  +  85  c.c.  H2O. 

15  c.c.  tV  normal  HCl  +  2|  c.c.  f  mol.  NaCl  +  82^  c.c.  H2O. 
15  c.c.  tV  normal  HCl  +  5  c.c.  f  mol.  NaCl  +  80  c.c.  H2O. 
tV  normal  HCl  +  10  c.c.  i  mol.  NaCl  +  75    c.c.  HoO. 


15  c.c 


15  c.c.  tV  normal  HCl  +  15  c.c.  f  mol.  NaCl  + 


c.c 


H2O. 


1 

■T 

^H  1 

^H  j 
^H  i 

]Hff 

rl^^^l 

1 

^Hj 

11 

^H 1 

mm 

■hj 

Q 

Fig.  6. 

The  relative  degree  of  solution  of  the  gelatine  after  a  residence  in 
these  mixtures  of  18  hours  is  indicated  in  Fig.  7.  The  addition  of  the 
salt  has  decreased  the  amount  of  the  gelatine  that  goes  into  solution 
in  the  hydrochloric  acid,  and  this  the  more  the  higher  the  concentra- 
tion of  the  added  salt. 

Experiment  7.  —  Five  leaves  of  dr>'  gelatine  weighing  altogether 
0.4  gram  and  having  the  same  surface  were  placed  in  each  of  the  fol- 
lowing solutions: 

1.  iscciVn.  HCl +85  c.c.  HoO. 

2.  15  c.c.  \Q  n.  HCl  +  10  c.c.  \  mol.  sodium  acetate  -f-  75  c.c.  HoO. 

3.  15  c.c.  T(y  n.  HCl  -f  10  c.c.  \  mol.  sodium  chloride  +  75  c.c.  HoO. 

4.  15  c.c.  tV  n.  HCl  -f  10  c.c.  \  mol.  sodium  nitrate  +  75  c.c.  HoO. 

5.  15  c.c.  tV  n.  HCl  -f  40  c.c.  \  mol.  disodium  hydrogen  phosphate 

+  45  c.c.  H2O. 


NEPHRITIS 


. 


Fig.  7. 


1 1 1'  11 ' 


l«llll« 


Fig. 


NEPHRITIS  19 

6.   15  c.c.  tV  n.  HCl  +  40  c.c.  \  mol.  sodium  sulphate  +  45  c.c.  H2O. 
7.15  c.c.  tV  n.  HCl  +  10  c.c.  T  mol.  sodium  citrate  +  75  c.c.  H2O. 

The  relative  amounts  of  gelatine  dissolved  in  these  various  solu- 
tions after  the  gelatine  leaves  had  with  occasional  agitation  remained 
in  them  for  19^  hours  are  indicated  in  Fig.  8.  As  is  readily  evident, 
each  of  the  salts  decreases  by  its  presence  the  amount  of  gelatine 
dissolved  in  the  acid  solution.  The  divalent  and  trivalent  anions  are 
more  powerful  in  this  respect  than  the  monovalent  ions,  with  the  ex- 
ception of  the  acetate.  The  intermediate  position  taken  by  this  ion, 
in  this  matter  of  the  solution  of  the  gelatine,  corresponds  with  the 
intermediate  position  occupied  by  this  same  ion  in  the  swelling  of 
the  colloid  under  similar  circumstances. 

It  is  clearly  apparent  from  what  has  been  said  that  the 
"  solution  "  of  two  typical  emulsion  colloids  (protein  gels) 
is  intimately  connected  with  the  character  of  the  medium 
in  which  these  gels  find  themselves.  Acids  (and  alkalies) 
favor  their  solution  while  various  other  substances  (notably 
salts)  either  do  not  affect  the  solubility  of  the  gel  at  all,  or 
if  present  in  conjunction  with  an  acid  (or  alkali)  depress  the 
amount  that  would  have  been  ''  dissolved  "  if  the  acid  (or 
alkali)  had  been  present  alone. 

We  will  now  adduce  the  evidence  which  is  intended  to 
show  that  the  colloidal  gel  that  constitutes  the  urinary  mem- 
brane goes  into  ^^  solution  "  in  the  urine  {albuminuria  results) 
under  the  same  conditions  under  which  fibrin  or  gelatine  gels 
go  into  "  solution  "  in  water. 

5.   Albuminuria    as    a    Phenomenon    Identical    with    the 
"  Solution  "  of  a  Protein  Gel. 

No  special  argument  is  necessary  to  prove  that  what  lies 
between  the  urine  on  the  one  hand  and  the  blood  on  the  other 
{the  kidney)  represents  physicochemically  a  colloidal  gel. 
The  general  physical  properties  of  the  kidney  as  a  whole 
betray  this  fact,  and  from  chemical  analysis  we  know  that 
the  albumins,  globulins,  higher  carbohydrates,  fats,  and 


20  NEPHRITIS 

"  lipoids  "  which  constitute,  exclusive  of  water,  the  bulk 
of  this  organ,  are  all  to  be  counted  in  the  group  of  our 
most  tj-pical  emulsion  colloids.  What  we  need  to  show  is 
that  under  normal  circumstances,  in  "  health,"  the  con- 
ditions are  such  as  to  keep  these  colloids  (as  we  are  dis- 
cussing albuminuria  this  means  the  proteins)  in  the  gel 
state,  while  under  other  circumstances  (for  example  in 
nephritis)  conditions  are  offered  which  permit  these  col- 
loids to  pass  over  into  the  sol  state  and  so  escape  with  the 
urine.  As  we  found  changes  in  the  reaction  of  the  medium 
to  play  a  most  important  role  in  the  '^  solution  "  of  such 
emulsion  colloid  gels  (fibrin  and  gelatine),  we  will  direct  our 
chief  inquiry  into  the  question  of  whether  such  changes 
occur  in  the  kidney  in  every  condition  characterized  by  an 
albuminuria.  An  ahnormal  production  or  accumulation  of 
acid  ijt  the  kidney  lies  at  the  bottom  of  every  albuminuria  and 
is  responsible  for  it.  Our  support  for  such  a  \dew  will  come 
from  three  directions. 

1.  Evidence  of  an  abnormal  production  or  accumulation 
of  acid  in  the  kidney,  or  conditions  predisposing  thereto, 
exist  in  every  case  of  albuminuria,  and  conversely; 

2.  Any  means  which  leads  to  an  increased  production 
or  favors  the  accumulation  of  acid  in  the  kidney  results 
in  albuminuria. 

3.  Any  means  by  which  we  can  decrease  the  ''  solu- 
bility "  of  various  protein  gels  (fibrin  and  gelatine)  in  an 
acid  medium  constitutes  a  means  by  which  we  can  decrease 
albuminuria. 

The  first  two  of  these  we  will  consider  at  once.  The 
third  we  will  take  up  separately  later  in  this  paper  when 
we  discuss  the  subject  of  the  treatment  of  nephritis. 


NEPHRITIS  21 

§   I. 

I.  If  albuminuria  is  to  be  regarded  as  a  process  of 
"  solution  "  of  the  urinary  membrane  in  consequence  of  the 
presence  of  acids  in  it,  then  evidently  the  maintenance  of 
the  gel  state  of  the  normal  membrane  must  be  intimately 
associated  with  a  maintenance  of  neutrality  in  it.  We  are 
therefore  first  of  all  interested  in  the  fact  that  (exclusive  of 
the  gastric  juice,  the  urine,  and  less  positively,  the  sweat, 
vaginal  secretion,  and  alimentary  contents  when  fat  is  fed) 
the  fluids  and  tissues  composing  the  living  mammal  are  to  all 
intents  and  purposes  neutral  in  reaction  and  are  capable  of 
maintaining  this  neutrality  against  the  introduction  of  con- 
siderable acid  into  them. 

In  the  terms  of  our  modern  physical  chemistry,  an  acid 
reaction  is  due  to  the  presence  of  free  hydrogen  ions,  an 
alkaline  reaction  to  the  presence  of  free  hydroxyl  ions.  A 
neutral  reaction  means,  therefore,  one  of  two  things:  either 
neither  of  these  ions  are  present,  or  else  just  as  many  of 
the  one  as  of  the  other,  so  that  they  balance  each  other  (the 
latter  is  the  case  in  the  body).  The  neutral  reaction  of 
the  blood  (and  from  this  it  has  been  generally  assumed  that 
the  tissues  themselves  are  also  neutral  in  reaction)  seems 
at  first  sight  a  rather  surprising  fact  when  considered  in 
the  light  of  our  older  teachings  that  the  body  fluids  and  the 
cells  are  all  "  alkaline."  But  these  older  teachings  are 
erroneous  for  they  are  based  upon  an  improper  interpreta- 
tion of  the  results  obtained  with  titration  methods.  The 
blood,  for  example,  has  generally  been  held  to  be  "  alkaline  " 
because  it  is  capable  of  neutralizing  acid.  But  as  we  know 
now,  the  power  of  a  solution  to  neutralize  an  acid  is  no  index 
of  its  content  of  free,  that  is  to  say,  active,  hydroxyl  ions 
which  is  the  true  measure  of  its  alkalinity.  For  a  proper 
measure  of  this  hydroxyl  ion  concentration  in  the  blood  (or 


22  NEPHRITIS 

in  the  tissues)  all  the  determinations  are  valueless  that 
antedate  the  fundamental  measurements  of  P.  Fraenkel,^ 
G.  Farkas,^  and  Rudolf  Hober  ^  who  first  used  proper  physico- 
chemical  methods  (so-called  gas  chains)  in  the  biological 
study  of  this  problem.  The  observations  of  all  these 
authors  agree  in  pronouncing  the  normal  blood  neutral  in 
reaction ;  as  neutral  as  pure  distilled  water. 

Of  further  interest  is  the  fact  that  this  state  of  neutrality 
of  the  blood  {and  of  the  tissues)  is  maintained  against  the  in- 
troduction of  considerable  acid  or  alkali  into  them.  When  ex- 
posed to  the  action  of  an  acid,  it  is  found  that  the  normal 
hydrox>'l  ion  concentration  of  the  blood  drops  with  the 
progressive  introduction  of  acid  into  it  in  the  form  of  a 
curve,  which  falls  only  very  slowly  at  first,  and  then  more 
rapidly.  Just  why  and  how  the  state  of  neutrality  is  thus 
maintained  for  a  period  does  not  at  this  particular  moment 
interest  us,  but  it  may  not  be  amiss  to  point  out  that  two 
factors  are  involved  in  the  process.  The  first  lies  in  the 
fact  that  such  salts  as  sodium  carbonate  and  disodium 
hydrogen  phosphate  are  capable  of  uniting  with  acids 
(carbonic  and  phosphoric  acids)  to  form  salts  having  a 
higher  hydrogen  content  (sodium  bicarbonate  and  sodium 
dihydrogen  phosphate),  but  which  in  their  dissociation 
yield  few  more  hydrogen  ions  than  the  salts  from  which 
they  were  originally  formed  and  which  were  present  in  the 
blood  to  start  with.  In  other  words,  there  is  for  a  time 
only  a  slight  increase  in  the  concentration  of  the  hydrogen 
ions  (increase  in  acidity)  in  spite  of  the  considerable  intro- 
duction of  free  acid  into  the  system.     (Z.  /.  Eenderson.y 

^  P.  Fraenkel:  Pfluger's  Archiv,  96,  6oi  (1903). 

2G.  Parkas:  Pfluger's  Archiv,  98,  551  (1903);  Archiv  f.  (Anat.  und) 
Physiol.,  Supplement,  517  (1903). 

3  Rudolf  Hobcr:  Pfluger's  Archiv,  81,  522  (1900);  99,  572  (1903). 

*L.  J.  Henderson:  American  Journal  of  Physiology,  16,  257  (1906);  21, 
169  (1908);  21,  427  (1908);  Ergebnisse  d.  Physiologic,  8,  257  (1909),  where 
extensive  references  to  the  literature  will  be  found- 


1 


NEPHRITIS  23 

The  other  and  lesser  element  for  the  maintenance  of  neu- 
trality resides  in  the  amphoteric  character  (that  is  to  say 
their  power  of  combining  either  with  acids  or  alkalies)  of 
the  colloids  found  in  the  blood  or  the  tissues.  The  albu- 
mins, for  example,  can  unite  with  considerable  quantities 
of  acid  (or  alkali)  without  any  decided  change  in  their  be- 
havior toward  indicators.  The  presence  of  certain  colloids 
in  any  system  will  therefore  serve  to  delay  the  increase  in 
the  concentration  of  the  hydrogen  ions  when  an  acid  is 
added  to  this  system.^  But  let  not  the  impression  be 
gained  from  these  remarks  that  the  blood  or  the  tissues  are 
not  sensitive  to  even  very  minute  additions  of  acid  (or 
alkali)  to  them.  Such  an  increase  in  the  concentration  of 
the  carbonic  acid  as  occurs  when  normal  arterial  blood  be- 
comes venous  is  already  sufficient  to  reduce  the  hydroxy! 
ion  concentration  in  the  latter  to  one  half  that  existing  in 
normal  arterial  blood.  How  profoundly  even  such  a 
change  affects  the  state  of  the  colloids  we  will  have  occasion 
to  discuss  later.  For  the  present  we  are  content  with  mak- 
ing the  point  that  the  blood  and  (presumably)  the  tissues  are 
neutral  in  reaction,  that  they  are  capable  of  maintaining  this 
neutrality  within  rather  wide  limits,  even  when  subjected  to 
the  action  of  an  acid,  and  that  in  consequence,  under  normal 
circumstances,  conditions  are  such  in  the  cells  of  the  kidney 
as  to  inaintain  the  colloids  here  in  their  gel  state. 

2.  As  modern  physicochemical  studies  have  reduced  what 
we  formerly  regarded  as  the  "  alkalinity "  of  the  blood 
to  a  point  where  we  may  call  it  neutral,  so  also  have  they 
reduced  the  normal  "  acidity  "  of  the  urine  from  what  we 
used  to  assume  this  to  be.     Just  as  the  neutralizing  power 

^  J.  Sjoqiiist:  Skand.  Arch.  f.  Physiol.,  5,  277  (1895);  Otto  Cohnheim: 
Zeitschr.  f.  Biol.,  33,  489  (1896);  K.  Spiro  and  W.  Pemsel:  Zeitschr.  f.  Physiol. 
Chem.,  26,  233  (1898),  5.  Bugarszky  and  L.  Liehermann:  Pfliiger's  Arch.,  72, 
51  (1898);  r.  B.  Robertson:  Jour,  of  Physical  Chem.,  11,  542  (1907);  12,  473 
(1908). 


24 


NEPHRITIS 


of  the  blood  for  acids  is  no  indication  of  its  true  reaction, 
so  also  is  the  amount  of  alkali  with  which  a  given  speci- 
men of  urine  will  combine  no  measure  of  its  true,  that  is  to 
say,  active,  acidity.  To  gauge  this  properly  the  concen- 
tration of  the  hydrogen  ions  in  it  must  be  determined  and 
this  was  not  done  until  von  Rhorer  ^  and  Rudolf  E'dher  ^  ap- 
plied the  principle  of  the  gas  chain  to  the  physicochemical 
analysis  of  the  urine.  The  following  Table  I,  taken  from 
Hoher,^  indicates  what  is  the  concentration  of  the  hydrogen 
ions  in  a  series  of  normal  morning  urines.  This  gives  a 
measure  of  their  true  acidity. 

TABLE  I.  — NORMAL  URINE. 


4 


Hydrogen  ion  acidity 
(IO-5  .  Ch). 

Titration  acidity. 

0.58 
0.52 
0.50 
0.46 
0.31 

0.046 
0.034 
0.042 
0.069 
0.075 

It  would  support  our  idea  of  the  cause  of  albuminuria  if 
it  could  be  shown  that  this  acidity  of  the  urine  increases  in 
conditions  associated  with  an  albuminuria.  How  strikingly 
true  this  is,  is  clearly  evident  from  the  following  analyses 
of  nephritic  urines  also  taken  from  E'dher  and  made  of 
course  without  thought  of  using  them  for  such  purposes  as 
we  do  here. 

As  is  clearly  evident  on  comparing  these  two  tables  the 
active  acidity  of  the  urine  of  nephritics  may  be  more  than 
four  times  that  of  the  normal  urine.  But  Table  II  already 
suffices  to  betray  another  fact.     The  highest  acidities  occur 

1  L.  von  Rhorer:  Pfliiger's  Archiv,  86,  586  (1901), 

2  Rudolf  Ilobcr:  Hofmeister's  Beitrage,  3,  525  (1903). 

3  Rudolf  Ilobcr:  Physikalische  Chemie  d.  Zelle  u.  d.  Gewebe.  Zweite  Aufl. 
158.     Leipzig,  1906. 


NEPHRITIS 


25 


in  the  acute  jorms  of  nephritis,  in  other  words,  in  the  same  forms 
in  which  we  find  most  albumin.  The  lowest  values  are 
found  in  the  chronic  interstitial  forms,  in  other  words,  in 
the  very  types  in  which  albumin  is  very  likely  to  be  found 
only  in  traces  or  at  times  not  at  all.  The  degree  of  the 
albuminuria  therefore  follows  very  closely  the  degree  of 
acidity.  We  shall  have  occasion  to  return  to  this  question 
later. 

TABLE   11. —  ABNORMAL  URINE. 


Hydrogen  ion 

acidity 

(10-5  -Ch), 

Titration  acidity. 

Remarks. 

2.34 
1.50 
0.84 
1. 10 
2.20 
2.10 
0.56 
0.67 

0.019"] 

0.018  ! 
0.027  f 
0.020J 
0.022  ) 
0.020  ) 
0.014  1 
0.050  ( 

Interstitial  nephritis. 

Acute  nephritis. 

Chronic  interstitial  nephritis. 

Let  us  now  look  at  the  columns  in  these  tables  that 
record  the  titration  acidities.  It  is  such  values  —  erro- 
neously interpreted  as  measures  of  the  true  acidity  of  the 
urine  —  that  we  find  recorded  in  all  the  studies  of  nephritis. 
When  the  individual  titration  acidities  in  the  above  tables 
are  compared  with  their  corresponding  active  acidities  as 
determined  by  measuring  the  hydrogen  ion  concentrations 
in  the  urine,  it  is  readily  apparent  that  the  two  values 
do  not  even  approximately  parallel  each  other.  What  is 
learned  when  the  titration  acidity  of  the  urine  is  determined 
is  its  capacity  to  neutralize  alkali.  Under  otherwise  con- 
stant conditions  it  is  clear  that  this  titration  acidity  of  the 
urine  must  grow  with  every  increase  in  the  amount  of  acid 
in  the  urine.  The  uniformly  higher  titration  acidity  of  the 
urine  in  nephritis,  as  is  shown  not  only  in  the  above  tables 
I  and  II  but  by  the  scores  that  may  be  found  in  any  of  the 


26  NEPHRITIS 

larger  works  that  deal  with  this  question  of  nephritis,  be- 
comes further  evidence  therefore  in  favor  of  our  contention  that 
an  abnormal  production  or  an  abnormal  accumulation  of  acid 
occurs  in  the  kidney  in  every  albuminuria. 

3.  In  the  same  way  that  we  use  the  increased  alkah  ca- 
pacity of  the  urine  as  e\idence  for  the  presence  of  abnor- 
mally large  amounts  of  acid  in  it  (and  so  in  the  kidney  cells 
from  which  this  comes),  so  also  may  w^e  use  the  decreased 
acid  capacity  of  the  blood  as  evidence  in  the  same  direction. 
The  titration  values  of  the  blood,  w^hich  the  older  clinical 
observers  looked  upon  as  indices  of  its  "  alkalinity,"  may 
be  drawn  upon  for  evidence  to  show  that  in  the  albumi- 
nurias there  exists  a  decreased  power  of  the  blood  to  neutral- 
ize acids.  As  studied  particularly  by  Rudolf  von  Jaksch,^ 
W.  H.  Rionpf,^  E.  Peiper  ^  and  F.  Kraus  ^  a  decrease  in  the 
acid  capacity  of  the  blood  is  noted  in  no  conditions  more 
strikingly  than  in  nephritis  and  its  oft  associated  urcEmia. 

4.  Our  argument  thus  far  has  shown  that  in  nephritis 
there  is  a  great  increase  in  the  true  acidity  of  the  urine,  and 
that  in  both  the  urine  and  the  blood  there  occur  changes 
in  the  titration  values  which  clearly  indicate  that  both  are 
holding  a  more  than  normal  amount  of  acid.  Our  knowl- 
edge of  physical  chemistry  (the  laws  of  chemical  equilibrium) 
permits  us  to  utilize  these  facts  as  e\adence  indicating  that 
the  tissues  of  the  kidney  which  He  between  the  urine  on 
the  one  hand  and  the  blood  on  the  other  (all  that  we  in 
our  definition  sum  up  as  the  urinar^^  membrane)  must, 
under  such  circumstances,  also  show  a  rise  in  acid  con- 
centration. But  it  would  further  strengthen  this  view  if 
we  could  bring  a  more  direct  proof  in  support  of  this  de- 

1  R.  V.  laksch:  Zeitschr.  f.  klin.  Medicin,  13,  350  (1887). 

2  W.  n.  Rumpf:  Centralbl.  f.  klin.  Medicin,  12,  441  (1881). 
»£.  Peiper:  Virchow's  Arch.,  116,  337  (1889). 

*F.  Kraus:  Zeitschr.  f.  Heilkunde,  10,  106  (1889);  Archivf.  exp.  Path.  u. 
Pharm.,  26,  181  (1889). 


NEPHRITIS  27 

duction.  It  would  be  well  of  course  if  wx  could  obtain  a 
direct  measure  of  the  hydrogen  ion  concentration  in  the 
kidney.  Gas-chain  methods  are  naturally  not  applicable 
to  solid  organs,  and  to  apply  them  to  the  expressed  juice 
of  the  kidney  would  be  to  introduce  so  many  errors  into 
the  whole  problem  as  to  render  the  conclusions  valueless. 
We  can,  however,  obtain  material  help  by  using  indicators. 

Proof  of  an  increase  in  the  amount  of  acid  held  by  the 
kidney  cells  in  conditions  associated  with  an  albuminuria 
is  furnished  by  the  following  facts : 

In  1885,  E.  Dreser  ^  described  a  series  of  experiments  on 
the  excretion  of  dyes  by  the  kidney  which  differed  from  the 
preceding  studies  of  this  subject  as  first  made  by  R.  Heid- 
enhain  ^  and  M.  Nussbaum,^  in  that  he  utilized  the  results 
of  his  experiments  in  an  attempt  to  get  an  answer  to  the 
question  as  to  where  in  the  kidney  the  acid  of  the  urine  is 
secreted.  Dreser  made  chief  use  of  acid  fuchsin  which  he 
injected  in  5  to  10  per  cent  solutions  (amounts  not  stated) 
into  the  dorsal  lymph  sacs  of  frogs.  This  dye  has  the 
property  of  being  red  in  aqueous  solution  only  in  the  pres- 
ence of  an  acid;  in  an  alkaline  solution  it  becomes  practi- 
cally colorless  (yellow).  Dreser  therefore  reasoned  that 
the  presence  of  a  red  color  in  any  tissue  after  the  injection 
of  this  dye  into  the  circulation  of  an  animal  was  evidence 
for  an  acid  reaction  in  that  tissue.  The  first  fact  noted  by 
Dreser  that  is  of  interest  to  us  is  that  after  a  single  dose  of 
acid  fuchsin  the  urine  is  found  shortly  thereafter  to  be- 
come brilHantly  red.  If  the  kidney  from  such  an  animal 
is  examined  no  stained  cells  are  noted  anywhere  in  the 
kidney.  To  interpret  this  fact  we  would  have  to  say  that 
normally  the  urine  is  acid  in  reaction  hut  the  cells  of  tJie 

1  H.  Dreser:  Zeitschr.  f.  Biol.,  21,  41  (1885);  ibid,  22,  56  (1886). 

2  R.  Heidenhain:  Pfliiger's  Archiv,  9,  i  (1875). 

^  M.  Nussbaum:  Pfliiger's  Archiv,  16,  141  (1878). 


28  NEPHRITIS 

normal  kidney  have  not  an  acid  reaction.     The  following 
may  serve  to  corroborate  this  finding  of  Dreser. 

Experiment  8.  —  Three  frogs,  weighing  35  grams  each,  are  in- 
jected, respectively,  with  0.25,  0.5,  and  i.o  c.c.  of  an  aqueous  i  per 
cent  acid  fuchsin  solution,  into  the  dorsal  lymph  sac.  All  are  seen  to 
secrete  a  red  colored  urine  before  being  killed.  They  are  killed  re- 
spectively after  i,  i^  and  4^  hours.  On  autopsy,  red  urine  is  found 
in  the  bladder  of  each  anitnal.  The  kidneys  are  not  stained.  They 
are  rapidly  removed  from  the  freshly  killed  animals,  frozen  with 
liquid  carbon  dioxide  gas  (on  a  Bardeen  freezing  microtome  where 
the  gas  does  not  come  in  contact  with  the  tissue)  and  sectioned. 
The  sections  are  immediately  transferred  to  a  slide  (without  being 
brought  in  contact  with  water  or  any  other  medium  except  air), 
covered  with  a  cover  slip,  and  examined  under  the  microscope. 
None  of  the  kidney  tissues  are  seen  to  he  stained.  To  be  sure  that  the 
freezing  plays  no  part  in  the  findings,  a  parallel  series  of  free-hand 
sections,  and  crush  preparations  of  the  kidneys  are  made.  No 
stained  cells  are  found. 

When  the  uncolored  sections  are  touched  with  very  dilute  acetic 
acid  they  are  seen  gradually  to  assume  a  pink  color.  Acid  fuchsin  is 
therefore  present  in  the  kidney  tissues,  but  as  cut  from  the  body  the 
reaction  of  this  organ  is  not  such  as  to  allow  its  red  color  to  appear. 
The  pink  tinge  visible  in  the  kidney  after  being  touched  with  acid  in- 
cludes the  glomeruli. 

ExPERniEXT  9.  —  To  show  that  what  was  said  for  the  frog  holds 
also  for  the  mammal,  two  young  rabbits,  weighing,  respectively,  184 
and  189  grams,  received  into  the  ear  veins  2.0  and  4.0  c.c,  respectively, 
of  a  I  per  cent  aqueous  acid  fuchsin  solution.  At  the  end  of  30  and 
35  minutes,  respectively,  they  were  killed  by  a  blow  on  the  head  and 
immediately  autopsied.  Light  red  urine  was  found  in  the  bladder  of 
the  first,  deep  red  urine  in  that  of  the  second.  The  appearance  of  the 
kidneys  in  both  animals  was  entirely  normal,  and  no  dye  was  visible 
in  the  kidneys  either  macroscopically  or  microscopically.  When  a 
little  very  dilute  acetic  acid  was  permitted  to  flow  under  the  cover 
slips,  the  sections"  turned  uniformly  pink. 

Drcscr  noted  no  staining  of  the  frog's  kidney  until  he 
had  repeated  his  acid  fuchsin  injections  several  times. 
Then  he  found  that  the  cells  of  the  convoluted  and  of  the 


NEPHRITIS  29 

straight  tubules  began  to  stain  red.  He  interpreted  this 
finding  by  saying  that  from  the  long-continued  effort  on 
the  part  of  these  cells  to  excrete  the  dye,  they  become 
fatigued  and  so  some  of  the  dye  remains  behind  to  be  dis- 
covered on  subsequent  section  of  the  kidney.  From  all 
these  facts  Dreser  concluded  that  the  acid  constituents  of 
the  normal  urine  are  "  secreted  "  by  the  convoluted  tubules, 
and  that  since  the  glomeruli  and  their  capsules  remain  un- 
stained, the  ''  urine  "  coming  from  these  must  be  '*  alkaline  " 
in  reaction,  to  change  to  an  acid  reaction  after  passing  by 
the  convoluted  tubules.  Whether  such  conclusions  are 
really  justified  we  shall  have  occasion  to  discuss  later. 

No  one  can  quarrel  with  the  simple  experimental  finding 
that  acid  fuchsin  does  not  stain  the  normal  kidney,  and 
does  do  this  after  repeated  and  long-continued  injections. 
Such  staining  of  the  kidney  Dreser  still  regards  as  '^  physi- 
ological." Strictly  speaking,  and  for  reasons  that  will  be 
apparent  as  we  go  on,  I  should  myself  be  more  inclined  to 
regard  it  as  "pathological."  What  Dreser  calls  the 
^^ fatigue  "  of  the  cells  of  those  portions  of  the  kidney  which 
stain  after  repeated  infections  of  the  acid  fuchsin,  we  are  per- 
fectly safe  in  regarding  as  the  first  evidences  of  an  abnormal 
acid  content  in  these  cells,  and  we  may  hold  that  the  repeated 
infection  of  this  dye  is  itself  responsible  for  such  a  condition. 

Acid  fuchsin  is  a  weak  acid,  and  must  produce  the  same 
effects  upon  the  kidney  that  we  know  are  produced  by  the 
injection  of  any  other  acid.^  After  the  injection  of  acids 
we  note  regularly  all  the  signs  of  a  nephritis,  and  that  these 
were  not  absent  in  Dreser's  experiments  is  clearly  evidenced 
by  the  "  anuria  "  which  this  author  so  often  noted  in  his 
frogs. 
Eut  Dreser  ^   describes  yet   another   experiment   which 

^  See  the  succeeding  §  2  on  page  35. 

^H.  Dreser,  Zeitschr.  f.  Biol.,  21,  53  (1885). 


30  NEPHRITIS 

shows  that  an  abnormal  production  or  storage  of  acid 
occurs  in  the  kidney  in  nephritis.  The  kidney  of  the  frog 
receives  a  blood  supply,  it  will  be  remembered,  from  two 
sources  —  through  the  renal  artery,  as  in  mammals,  and 
through  a  sort  of  portal  system  analogous  to  that  existing 
in  the  liver.  The  blood  from  both  these  sources  mixes  to 
leave  the  kidney  by  way  of  the  renal  vein.  Dreser  noted 
that  if  acid  Jiichsin  is  injected  into  the  abdominal  vein  an  hour 
after  the  renal  artery  has  been  tied,  the  co7ivoliited  tubides  stain 
red.  As  already  pointed  out,  no  such  red  staining  of  the 
cells  is  noted  if  the  dye  is  so  injected  without  ligature  of 
the  renal  artery.  Dreser  interprets  his  finding  in  terms  of 
physiolog}',  but  that  we  deal  here  with  a  pathological  con- 
dition of  the  kidney  —  a  nephritis  —  is  evidenced  not  only 
by  the  fact  noted  by  Dreser,  that  kidneys  so  treated  secrete 
no  urine,  but  by  the  evidence  furnished  below,  ^  that  after 
occlusion  of  the  arterial  blood  supply  to  the  kidney,  acid 
develops  in  this  organ,  the  kidney  swells,  the  water  secre- 
tion falls,  and  casts  and  albumin  appear  in  the  urine. 

Further  tinctorial  evidence  of  an  abnormal  production  or 
accumulation  of  acid  in  the  kidney  in  nephritis  is  furnished 
by  certain  experiments  of  R.  Hetdenhain,  M.  Nnssbatim, 
and  P.  Grutzner  with  sodium  indigosulphonate.  This  dye 
behaves  in  a  way  entirely  similar  to  that  of  acid  fuchsin. 
It  is  deep  blue  or  indigo  in  an  acid  solution  and  yellow  in 
an  alkaline  solution.  The  somewhat  contradictory  conclu- 
sions of  these  authors,  based  on  their  studies  with  this 
dye,  are  easily  put  in  order  if  we  try  to  separate  those  of 
their  findings  which  are  pathological  from  those  which  are 
physiological.  In  my  own  experiments  on  rabbits  and  frogs, 
I  have,  first  of  all,  never  been  able  to  confirm  any  but 
the  conclusion  of  Niissbanm  ^  that  no  part  of  the  normal 

*  See  pages  50,  123  and  151. 

*if.  Ntissbaum:  Pfliiger's  Archiv,  16,  141  (1878). 


NEPHRITIS  31 

kidney  stains  with  sodium  indigosulphonate.  This  corrobo- 
rates the  finding  obtained  with  acid  f uchsin  —  the  normal 
kidney  is  not  acid  in  reaction. 

Experiment  10.  —  Four  frogs,  weighing  30  grams  each,  are  in- 
jected, respectively,  with  0.25,  0.5,  i.o,  and  0.25  c.c.  of  a  i  per  cent 
aqueous  sodium  indigosulphonate  solution  into  the  dorsal  lymph  sac. 
Blue  urine  is  voided  by  each  of  the  animals  before  being  killed. 
After,  respectively,  40  minutes,  50  minutes,  70  minutes,  and  3I  hours, 
their  heads  are  cut  off  and  they  are  autopsied.  Blue  urine  is  found  in 
the  bladders  of  the  last  three.  ^Macroscopic  examination  shows  no 
color  anywhere  in  the  kidneys  of  these  animals,  and  microscopic  exami- 
nation of  frozen  sections  only  confirms  this  fact. 

Experiment  ii .  —  Three  rabbits  from  the  same  litter,  and  weigh- 
ing 497,  575,  and  447  grams,  respectively,  receive,  respectively, 
through  the  ear  vein,  i,  2,  and  5  c.c.  of  a  i  per  cent  aqueous  sodium 
indigosulphonate  solution.  They  are  killed  by  a  blow  on  the  head 
one  hour  after  being  injected.  Blue  urine  is  found  in  the  bladder  of 
each.  This  is  also  present  in  the  ureter  of  the  third.  The  kidneys 
are  entirely  unstained  in  the  first  two,  and  no  color  is  found  anywhere 
in  the  frozen  sections  prepared  from  these  kidneys.  The  kidney  of 
the  third  animal  has  a  mottled  blue  appearance  superficially,  and  one 
section  shows  some  blue  streaks  radiating  toward  the  pelvis  of  the 
kidney.  Frozen  sections  show  no  dye  anywhere  in  the  kidney  substance 
proper.  The  blue  streaks  are  due  to  dye  found  in  the  lumina  of  a  few 
of  the  collecting  tubules. 

In  apparent  contradiction  to  this  simple  conclusion  that 
the  normal  kidney  does  not  stain  with  sodium  indigo- 
sulphonate, stand  the  classical  experiments  of  Heidenhain,^ 
who  found  certain  portions  of  the  kidney,  notably,  again, 
the  convoluted  tubules,  to  stain  when  the  "secretion  of  the 
urine  was  sufficiently  depressed."  Heidenhain  brought 
about  the  desired  reduction  in  the  secretion  of  urine  by 
such  procedures  as  transverse  section  of  the  spinal  cord  in 
the  neck.     But  as  he  himself  has  noted,  this  produces  an 

^  R.  Heidenhain:  Pfliiger's  Archiv,  9,  i  (1875);  Hermann's  Handbuch  d. 
Physiol.,  5,  346.     Leipzig,  1883. 


32 


NEPHRITIS 


enormous  fall  in  blood  pressure.  Such  a  fall  in  blood 
pressure  does  not,  however,  leave  the  kidney  in  a  normal 
condition  —  it  spells  not  alone  an  anuria  but  an  albumi- 
nuria, and  casts,  in  other  words,  a  "nephritis."  The  staining 
of  the  kidney  under  these  circumstances  is  again  evidence  of  an 
abnormal  production  or  accumulation  of  acid  in  this  organ,  a 
conclusion  that  we  shall  shortly  be  able  to  corroborate  by 
entirely  different  methods. 

Both  Heidenhain  and  Dreser  have  laid  special  stress  on 
the  fact  that  the  convoluted  tubules  stain  under  the  con- 
ditions offered  in  their  experiments,  while  the  glomeruli  re- 
main unstained,  because  it  is  upon  this  fact  chiefly  that 
they  (and  their  followers)  have  based  their  conclusion  that 
the  different  parts  of  the  uriniferous  tubule  in  its  course 
from  the  glomerulus  to  the  pelvis  of  the  kidney  have  differ- 
ent functions.  As  generally  held,  these  dift'erent  parts  are 
supposed  to  secrete  into  (or,  according  to  Carl  Ludwig, 
absorb  from)  the  mother  urine,  —  the  liquor  postulated  by 
IF.  Boivman  to  be  separated  from  the  blood  in  its  passage 
through  the  glomeruli,  —  as  this  flows  down  the  uriniferous 
tubules,  the  different  substances  which  serve  to  character- 
ize the  urine.  Now,  I  do  not  myself  question  the  proba- 
bility that  the  different  portions  of  the  uriniferous  tubules 
have  different  functions,  but  strictly  speaking,  this  is  not 
proved  by  these  particular  experiments.  The  findings  of 
Dreser  and  Heidenhain  show  only  that,  under  the  conditions 
of  their  experiments,  the  neutrality  mechanism  existing  in  the 
convoluted  tubules  is  broken  down  more  easily  than  that  exist- 
ing, for  example,  in  the  glo7neruli.  That  this  approximates 
more  nearly  a  correct  interpretation  of  the  observed  phe- 
nomena is,  as  a  matter  of  fact,  indicated  by  the  following: 

By  simply  continuing  the  conditions  which  were  men- 
tiofied  as  effective  in  leading  to  a  staining  of  the  convoluted 
tubules,  we  get  a  staining  of  the  glomeruli.     Evidence  for  the 


NEPHRITIS  33 

correctness  of  this  conclusion  can  be  adduced  even  from 
some  cursory  experiments  mentioned  by  Heidenhain  and 
Griitzner.  As  pointed  out  above,  the  conditions  which 
lead  to  a  staining  of  certain  portions  of  the  kidney  with 
acid  fuchsin  or  sodium  indigosulphonate  (excessive  acid  in- 
jection, ligature  of  renal  artery,  gross  falls  in  blood  pres- 
sure) are  conditions  which  we  can  show  by  other  means  to 
be  such  as  are  associated  with  an  abnormal  production  or 
accumulation  of  acid  in  the  kidney.  No  matter  how  we 
interfere  with  a  proper  blood  supply  to  the  kidney  we  get 
such  a  production  of  acid.  It  does  not  therefore  surprise 
us  to  note  that  when  P.  Griitzner  ^  produced  circulatory 
disturbances  in  the  kidney  by  injecting  gum  arable,  he 
noted  not  only  the  development  of  anuria  and  albumi- 
nuria, but  he  found  at  the  same  time  that  the  glomeruli  and 
their  capsules  now  stained  with  sodium  indigosulphonate. 
Quite  as  simply  can  we  interpret  Heidenhain^ s^  finding  that 
the  glomerular  tufts  stain  with  sodium  indigosulphonate 
when  the  ureters  are  ligated.  When  this  is  done  the  urine 
is  dammed  back  and  accumulates  in  the  space  between  the 
glomerular  tuft  and  the  parietal  layer  of  the  capsule,  in  con- 
sequence of  which  the  capillaries  composing  the  tuft  are 
compressed,  so  that  the  normal  circulation  of  blood  cannot 
now  occur  through  them.  Under  these  circumstances  an 
abnormal  production  or  accumulation  of  acid  in  the  cells 
of  the  glomerulus  and  the  capsule  is  rendered  possible  and 
so  the  tissues  making  up  these  structures  now  stain. 

One  can  further  test  the  soundness  of  the  reasoning  de- 
tailed here,  namely,  that  a  staining  of  the  kidney  as  a  whole 
or  in  part  marks  the  presence  of  an  acid,  by  working  with 
excised  kidney.  Slices  of  fresh  kidney  kept  in  dilute  solu- 
tions of  sodium  indigosulphonate  or  acid  fuchsin  stain  only 

ip.  Grutzner:  Pfliiger's  Archiv,  24,  461,  1882. 

'  R.  Heidenhain:  Hermann's  Handbuch  d.  Physiol.,  5,  372 .    Leipzig,  1883. 


34 


NEPHRITIS 


very  slowly  and  very  slightly.  Hours  elapse  before  even  a 
faint  tinging  of  the  tissues  of  the  kidneys  results.  But  let 
a  trace  of  acid  be  added  and  all  parts  of  the  section  may  be 
made  to  stain  a  deep  blue  in  a  few  minutes.  In  the  same 
way  a  section  of  tissue  from  a  kidney  that  has  been  dead 
some  time  (and  so  contains  post  mortem  acids)  stains 
readily,  and,  let  it  be  noted,  in  all  its  parts. 

It  will  be  recalled  by  anyone  familiar  with  such  studies 
as  those  of  Heidenhain,  Dreser,  or  the  numerous  investi- 
gators who  since  their  day  have  adopted  similar  experi- 
mental methods,  that  these  studies  are  intended  to  throw 
light  on  the  problem  of  secretion  by  the  kidney  cells.  This 
process  of  secretion  is,  of  course,  made  up  of  two  parts,  the 
one  concerned  with  the  taking  up  from  the  blood  of  the 
substance  to  be  secreted,  the  other  with  the  giving  off 
of  this  same  substance  in  the  urine.  The  problems  in- 
volved here  are  discussed  in  detail  later,  but  it  may  not  be 
amiss  to  point  out  even  now  that  what  is  so  often  done, 
namely,  the  regarding  of  a  mere  staining  of  some  or  all 
of  the  cells  of  an  organ  as  dependable  evidence  indicating 
that  the  dye  is  ''  secreted  "  by  these  cells,  is  entirely  wrong. 
The  presence  of  a  dye  in  a  cell  does  not  mean  this;  nor 
when  cells  stain  unequally  does  it  mean  that  those  most 
deeply  stained  are  most  involved  in  this  process.  It  may 
mean  just  the  reverse.  The  staining  of  the  excised  kidneys 
described  above  shows  this  very  clearly.  A  kidney  touched 
with  a  little  acid,  or  one  showing  post  mortem  change, 
stains  better  than  a  normal  kidney,  and  this  without  any 
hope  of  subsequently  "  secreting "  the  absorbed  dye. 
Again,  a  kidney  rendered  "  nephritic  "  by  ligation  of  its 
arterial  blood  supply  stains  better  than  a  normal  one, 
and  yet  no  one  would  maintain  that  a  nephritic  kidney 
"  secretes  "  all  dissolved  substances  better  than  a  healthy 
one. 


NEPHRITIS  35 

What  really  happens  in  the  excised  kidneys,  or  in  the 
^'  nephritic  "  kidneys  contained  in  the  still  Uving  animal, 
represents  but  an  isolated  expression  of  the  general  laws 
that  we  to-day  know  to  underlie  all  that  is  comprised  in  the 
physical  chemistry  of  the  dyestuffs.  The  kidney  cells  in 
the  experiments  that  have  been  detailed  are  stained  for  the 
same  reason,  and  their  staining  reactions  mean  the  same  thing, 
as  when  any  ordinary  lyophilic  colloid  such  as  fibrin  or  gela- 
tine takes  up  acid  fuchsin  or  sodium  indigosulphonate.  If 
these  colloids  are  seen  to  be  stained  red  or  blue  it  means, 
first  of  all,  that  they  have,  under  the  conditions  of  our  ex- 
periment, an  acid  reaction.  But  with  a  given  concentra- 
tion of  the  dye  the  depth  of  the  staining  becomes  a  measure 
of  the  degree  of  such  an  acid  reaction,  for  a  given  colloid 
will  absorb  the  more  of  any  so-called  "  acid  stain  "  the 
higher  the  concentration  of  the  acid  in  which  it  finds  itself. 
Other  things  being  equal,  the  kidney  cells  must  stain  the 
more  intensely  with  acid  fuchsin  or  sodium  indigosulpho- 
nate, the  higher  the  acid  concentration  developed  in  them. 
To  this  whole  question  we  shall  have  to  return  later. 

§2- 

We  are  now  ready  to  discuss  the  converse  of  what  has 
gone  before,  and  so  try  to  show  that  any  means  by  which 
we  can  bring  about  an  abnormal  production  or  accumulation 
of  acid  in  the  kidney  constitutes  a  method  of  producing  an 
albuminuria. 

I.  The  simplest  way  to  upset  the  normal  conditions  of 
neutrality  as  existing  in  the  kidney  lies,  of  course,  in  the  in- 
troduction into  this  organ  of  an  acid  of  some  kind.  This  is 
done  most  easily  by  injecting  the  acid,  either  in  solution  in 
water  or  in  a  "physiological"  salt  solution,  directly  into 
the  general  circulation  of  an  animal.  For  this  purpose  I 
used,  in  my  own  experiments,  a  large-sized  aspirating  syringe 


36 


NEPHRITIS 


with  a  two-way  valve,  rubber  tubing,  and  a  hypodermic 

needle,  as  illustrated  in  Fig.  9. 
The  acid  solution  wanned  to 
37°  C.  is  sucked  into  the  syringe 
through  the  tube  a.  After  turn- 
ing the  valve  v  it  can  be  ejected 
on  lowering  the  plunger  through 
the  tube  b,  which  ends  in  the 
hypodermic  needle  n.  The 
needle  is  inserted  into  the  ear 
vein  of  a  rabbit  and  is  held  in 
place  by  a  couple  of  small  artery 
forceps.  As  the  acid  is  injected 
intravenously,  one  observes  the 
normally  alkaline  urine  of  the 
rabbit  to  turn  acid,  and  as  this 
acidity  rises,  albumin  appears 
in  the  urine.  The  following  ex- 
periments dealing  with  the  ef- 
fects of  such  intravenous  acid 
injections  will  serve  to  illustrate 
this  point.  Let  it  be  noted 
that  in  addition  to  the  appear- 
ance of  albumin  in  the  urine, 
this  comes  to  contain  various 
casts,  epithehal  cells,  blood  cor- 
puscles, and  haemoglobin.  By 
comparing  the  urinary  output 
in  these  animals  with  that 
shown  by  normal  animals,  as 
detailed  further  on,  it  is  evident 
that  this  is  decreased.  Evi- 
dences of  an  oedema  are  also  not  wanting;  animals  injected 
with  an  acid  do  not  excrete  the  water  that  is  injected  with 


Fig. 


NEPHRITIS 


37 


this  acid  as  does  a  normal  animal  that  is  given'^water  only. 
The  water  when  injected  with  an  acid  is  retained  in  the  body, 
but  to  this  phase  of  the  problem  of  nephritis  we  shall  need 
to  return  later.  For  the  present  it  is  clear  that  there  develop 
all  the  most  typical  signs  of  an  acute  nephritis  when  acid  in 
sufficient  amount  is  injected  into  an  animal. 

Experiment  12.  —  Belgian  hare;  weight  1870  grams.  Has  been 
fed  corn,  oats,  hay,  and  cabbage.  Urine  obtained  by  gentle  man- 
ual pressure  over  the  bladder.^  In  the  time  of  the  experiment  there 
are  injected,  at  37.0°  C.  and  at  a  uniform  rate,  with  the  excep- 
tions noted,  291  c.c.  of  the  following  mixture:  300  c.c.  2V  normal 


HCl  +  20  c.c 

f  molecular  NaCl. 

Amount  of 

Time. 

urine  in  cubic 
centimeters. 

Remarks. 

1.20 

— 

Tied  to  animal  board.     No  anaesthetic. 

1-45 
2.00 

4.0  ) 
6. of 

Turbid,  yellow,  no  albumin,  no  casts. 
Injection  into  ear  vein  begun. 

2.15 

Fe 

w  drops 

Turbid,  yellow,  no  albumin,  no  casts. 

2.30 

1.9 

Clear,  yellow,  faint  trace  albumin,  no  casts. 

2.45 

•'\ 

Clear,  brownish  tinge,  albumin  present,  few 

3.00 

red  blood  corpuscles,  isolated  kidney  cells, 

no  casts. 

3-15 

1.6      1 
1-3      1 

Smoky  urine,  albumin,  isolated  granular  and 

3-30 

epithelial  casts. 

( 

Smoky  urine,  albumin,  isolated  granular  and 

3-45 

-   \ 

epithelial  casts.     Injection  interrupted  for 
2^  min. 
Smoky  urine,  albumin,  isolated  granular  and 

4.00 

1 

4.8      \ 

epithelial  casts.     Injection  interrupted  for 
5  min. 
Smoky  urine,  albumin,  isolated  granular  and 

415 

I 

) 

epithelial  casts.     Hasmoglobinuria.     Injec- 

4-45 

1 

21.0      i 

tion  interrupted  for  10  minutes. 

5-00 

J 

Animal  dies. 

Total  urine  secreted  since  beginning  injection  34.3  c.c. 

Autopsy.  — Weight  of  animal  2135  grams!  No  free  fluid  in  peri- 
toneal, pericardial,  or  pleural  cavities.  Kidneys  slightly  bluish,  and 
bleed  freely  on  section.     Nothing  about  them  is  strikingly  abnormal. 

^  In  these  experiments  on  albuminuria  the  greatest  care  is  necessary  not 
to  injure  the  lower  urinary  passages  and  so  get  a  bleeding  that  might, 


38 


NEPHRITIS 


Experiment  13.  —  Belgian  hare;  weight  2008  grams.  Has  been 
fed  a  mixed  diet  of  corn,  oats,  hay,  and  cabbage.  Urine  obtained  by 
gentle  pressure  over  bladder.  During  the  course  of  the  experiment 
there  are  injected  at  37.0°  C,  and  at  a  uniform  rate  with  the  ex- 
ception noted,  90  c.c.  of  the  following  mixture:  90  c.c.  to  normal  HCl 
plus  6  c.c.  I  molecular  NaCl. 


Amount  of 

Time. 

urine  in  cubic 
centimeters. 

Remarks. 

3-35 

Tied  down.     No  anaesthetic. 

3  40 

Injection  into  ear  vein  begun. 

6.0       1 

Turbid,  yellow,  alkaline  to  litmus.     No  al- 

3-55 

buminuria,  no  casts. 

4.05 

1-7 

Clearer,  trace  of  albumin  present. 

Urine  smoky,  albumin  increasing.     Injection 

4.20 

0.8      I 

stopped  for  15  minutes  as  animal  threatens 
to  die. 

4.40 

( 

Injection  recommenced. 

Bloody,  much  albumin,  red  blood  corpuscles 

4-45 

Few  drops  < 

are  present,   filled  with  granular  casts  of 
various  sizes. 

4.47 

Animal  dies. 

Total  urine  secreted  since  commencing  injection  8.5  c.c.  (+) 
.4 utopsy.  —  Weight  2087.5.    No  free  fluid  in  the  peritoneal,  pleural, 
or  pericardial  cavities.     Kidneys  sHghtly  swelled.     Under  the  cap- 
sule appear  tiny  haemorrhagic  points. 

through  the  presence  of  albumin  and  blood  in  the  urine,  lead  to  the  erroneous 
conclusion  that  a  nephritis  is  at  hand  when  only  some  bleeding  is  occurring 
into  the  bladder  or  urethra.  ^Manual  pressure  over  the  bladder  must  be 
made  with  gentleness,  and  care  must  be  taken  not  to  so  crowd  the  bladder 
into  the  pelns  as  to  kink  the  urethra.  Only  thesmallest  soft  rubber  catheter, 
well  vaselined,  must  be  introduced.  If  these  precautions  are  not  followed, 
fallacious,  if  not  worthless,  results  are  obtained.  When  an  animal  dies  or  is 
killed,  the  lower  urinary  passages  must  be  examined  for  haemorrhagic  points. 


NEPHRITIS 


39 


Experiment  14.  —  Belgian  hare;  weight  2259  grams.  Diet  un- 
known, as  he  has  just  been  received  in  the  laboratory.  Urine  obtained 
with  a  catheter.  In  the  course  of  the  experiment  75  c.c.  of  the 
following  solution  are  injected  at  a  uniform  rate,  with  the  exception 
noted:  75  c.c.  h  normal  HCl  plus  5  c.c.  f  molecular  NaCl. 


Time. 


Amount  of 
urine  in  cubic 
centimeters. 


Remarks. 


11.30 


11-45 

12.00 
12.15 
12.30 
12  .40 

12.45 


1-45 


7.0 


19.4 


0.4 
1.6 


3.7      \ 


II-5 


Tied  to  animal  board.  Urine  thick,  chrome 
yellow,  no  albumin. 

Thick,  chrome  yellow,  no  albumin,  alkaline 
to  litmus  paper. 

Injection  into  vein  of  ear  begun. 

Thick,  chrome  yellow,  no  albumin,  alkaline 
to  litmus. 

Clearer,  pinkish  tinge,  albumin  present. 

Injection  stopped  entirely. 

Urine  distinctly  red,  much  albumin,  many 
casts. 

Urine  turbid,  red,  shows  spectrum  of  oxyhae- 
moglobin,.  filled  with  albumin,  casts,  (epi- 
thelial, granular,  and  mixed)  epithelial  cells, 
and  red  blood  corpuscles.  Animal  released 
in  good  condition,  returned  to  hutch. 


Total  urine  secreted  since  beginning  injection  19.2  c.c. 


530 

Next 
morning 


50 
per  cathe- 
ter. 


370 

per  cathe--< 

ter. 


Clear,  yellow,  acid.  Casts  and  albumin  still 
present. 

Dark  amber,  thick,  faintly  acid,  clear.  Mi- 
croscopic examination  shows  many  squa- 
mous epithelial  cells  and  isolated  casts. 
Carefully  filtered  urine  shows  a  trace  of 
albumin. 


It  SO  happens  that  the  sum  total  of  the  chemical  changes 
that  go  on  in  the  living  animal  organism  are  of  such  a 
character  as  to  threaten  the  normally  neutral  reaction  ex- 
isting in  the  tissues  chiefly  from  the  acid  side.  Even  under 
normal  conditions,  the  tissues  have  to  guard  themselves 
against  becoming  acid  in  reaction.  Do  we  not  have  to 
count  carbonic  acid  among  the  chief  end  products  of  the 
oxidation  of  our  foodstuffs?    This  normal  tendency  of  the 


40  NEPHRITIS 

tissues  to  become  acid  in  reaction  is  enormously  increased 
under  various  pathological  conditions,  and  as  we  shall  find 
these  conditions  to  be  just  such  as  are  likely  to  lead  to  a 
nephritis,  the  discussion  of  this  subject  will  naturally  tend 
to  center  about  a  discussion  of  the  conditions  which  favor 
such  an  abnormal  production  or  accumulation  of  acids  in 
•the  tissues.  An  abnormally  high  alkali  content  in  the 
cells  under  normal  circumstances  is  scarcely  possible,  and 
when  it  is  induced  artificially  it  is  difficult  to  maintain,  for 
the  normal  acid  production  (CO2  production)  in  the  living 
cell  tends  quickly  to  neutralize  it.  The  question  of  an 
abnormally  high  alkali  content  of  the  cells  is  therefore 
scarcely  to  be  considered  in  our  further  discussion  of  the 
problem  of  nephritis.  And  yet  from  a  theoretical  stand- 
point it  is  quite  as  important  as  that  upon  which  we  shall 
lay  the  greater  stress.  As  we  pointed  out  in  our  discussion 
of  the  "  solution  "  of  colloidal  protein  gels  (such  as  fibrin 
or  gelatine)  these  colloids  go  into  "  solution "  quite  as 
readily  in  alkalies  as  in  acids.  Therefore,  even  though  an 
abnormally  high  alkali  content  is  scarcely  to  be  considered 
as  a  cause  of  "nephritis"  in  living  animals  (except  in 
cases  of  poisoning  with  alkalies)  we  should,  on  the  basis  of 
our  colloidal  conceptions  of  nephritis,  be  able  to  induce  this 
condition  experimentally  almost  as  easily  through  alkalies  as 
through  acids.  As  the  following  experiments  show,  this  is 
actually  the  case. 


NEPHRITIS 


41 


Experiment  15.  —  Belgian  hare;  weight  2085  grams.  Has  been 
fed  hay,  oats,  corn,  and  cabbage.  In  the  course  of  the  experiment 
there  are  injected  intravenously  at  a  uniform  rate  125  c.c.  of  the  fol- 


lowing mixture:  150  c.c. 
NaCl. 


:V  normal  NaOH  plus  10  c.c.  f  molecular 


Time. 


Amount  of 
urine  in  cubic 
centimeters. 


Remarks. 


2.35 

3-15 

330 

3-45 
4.00 

415 

4-30 
4-45 

4.58 


31- 
0.7 

1.2 
.8.4 
6.0 

1.2 


0.7 
0.4 


0.4+ 


0.6  con- 
tained 
in  cathe- 
ter. 


Catheterized.  Dark  amber,  acid  to  litmus 
paper.     No  albumin.     No  casts. 

Catheterized.  Weighed.  Placed  in  animal 
board.  Injection  into  ear  begun.  No  al- 
bumin.    No  casts.     Acid  in  reaction. 

Urine  clearer.  Acid  in  reaction  (?).  Trace 
of  albumin  (?). 

Milky,  alkaline  to  litmus.  Faint  trace  of 
albumin. 

Milky,  alkaline  to  litmus.  Also  isolated  casts. 
Faint  trace  of  albumin. 

Milky,  alkaline  to  litmus.  More  albumin. 
Many  long  hyaline  casts  with  coarsely 
granular  material  sticking  to  them. 

Milky,  alkaline  to  litmus.  Much  albumin. 
Filled  with  casts.  Bloody  tinge  to 
urine. 

Milky,  alkaline  to  litmus.  Much  albumin. 
Filled  with  casts.  Bloody  tinge  to  urine. 
Animal  dies. 

i.o  gram  of  faeces  lost.  It  is  noted  that  the 
albumin  reactions  as  obtained  with  cold 
nitric  acid  applied  to  the  filtered  acidified 
urine  are  not  as  intense  as  in  the  albuminu- 
rias induced  by  acid  injections.  (Less  al- 
bumin ?). 


Total  urine  since  beginning  injection  18.9  c.c. 

Autopsy.  —  Weight  2187  grams!  No  fluid  in  the  cavities.  In- 
testinal contents  seem  somewhat  more  fluid  than  usual.  Kidneys  are 
firm,  apparently  somewhat  swelled,  and  do  not  bleed  easily. 


42 


NEPHRITIS 


Experiment  i6.  —  White  rabbit;  weight  1911  grams.  Fed  hay, 
oats,  corn,  and  greens.  In  the  course  of  the  experiment  there  are 
injected  at  a  uniform  rate  185  c.c.  of  the  following  mixture:  225  c.c. 
T^j  normal  NaOH  plus  15  c.c.  f  molecular  NaCL 


Time, 


215 


2.30 


430 


Amount  of 
urine  in 

cubic  centi- 
meters. 


85. 


0.7       I 


2-45 

0.7 

300 

0.  2 

315 

1 .0 

330 

6.4 

3-45 

15-5 

4.C50 

22.0 

4-15 

24-5 

4.2s 

23 


o      \ 


Remarks. 


Catheterized.     Turbid,  dark  amber,  acid.     No 

albumin,  no  casts. 
Turbid,    dark    amber,    acid.     No   albumin,    no 

casts. 
Weighed.     Injection  into  ear  vein  begun. 
Urine  as  before. 
Neutral  to  litmus.     Clearer.     Small  amount  of 

albumin.     Many   hyaline   casts.     Some   have 

coarse  granules  in  them. 
Urine    clear   as    water.     Many   hyaline    casts. 

Some  have  coarse  granules  in  them. 
Urine  clear  as  water.     Only  a  few  casts  can  be 

found.     Albumin  present. 
Weakly    alkaline.     Albumin   present.     Isolated 

casts  only  can  be  found. 
Albumin  present.     No  casts  can  be  found.     The 

urine  has  a  pink  tinge  (haemoglobinuria).     No 

red  blood  corpuscles  microscopically. 
Injection  stopped. 
Faintly  alkaline.     Clear,  pink,  no  casts,  no  red 

blood  corpuscles.     Albumin  present.     Animal 

released.     Seems  entirely  normal,  and  eats  at 

once.     Weight  2000  grams! 


NEPHRITIS 


43 


Experiment  1 7.  — White  rabbit;  weight  2177  grams.  Fed  hay, 
oats,  corn,  and  cabbage.  In  the  course  of  the  experiment  there  are 
injected  at  a  uniform  rate  240  c.c.  of  the  following  mixture:  225  c.c. 
2V  normal  NaOH  plus  15  c.c.  |  molecular  NaCl.  Injection  made 
into  ear  vein. 


Amount  of 

urine  in 
cubic  cen- 
timeters. 


I  drop 


0.5 


drops 


•IS 

13.0 

•30 

12.0 

■45 

16.0 

.00 

19.0 

•IS 

23.0 

Remarks. 


Catheterized.     Turbid,    yellow   urine.     No    al- 
bumin.    No  casts. 
Weighed. 
No  albumin.     Injection  begun. 

Albumin  present.  Filled  with  casts,  mainly 
hyaline  in  character,  but  some  are  finely 
granular.  Much  squamous  epithelium  and 
cell  detritus. 

Alkaline  to  litmas.  Albumin  and  casts  as  before, 
but  all  the  casts  are  hyaline  except  for  coarse, 
granular  material  contained  in  or  attached  to 
some. 

Strongly  alkaline.     Albumin  and  casts  as  before. 

Strongly  alkaline.  Albumin  and  casts  as  before. 
The  urine  has  a  pinkish  tinge  (haemoglobi- 
nuria). 

Strongly  alkaline.  Albumin  and  casts  as  before. 
Urine  pinkish  (haemoglobinuria).  Red  blood 
corpuscles  are  found  and  two  microscopic 
blood  coagula.  This  bleeding  is  attributed  to 
traumatism  (animal  struggled  and  whipped 
catheter  about). 

Urine  strongly  alkaline.  The  animal  has  begun 
to  shiver  (acid  production!)  during  the  last  15 
minutes.  The  previously  warm  ears  are  pale 
and  cold. 

The  urine  becomes  faintly  alkaline,  then  scarcely 
affects  either  red  or  blue  litmus.  The  urine  is 
clear  like  water  except  for  a  clouding  due  to 
(traumatic)  blood.  Careful  search  of  the  sed- 
imented  urine  reveals  only  an  occasional  cast. 
The  animal  is  shivering  constantly.  It  is 
killed. 


Total  urine  since  beginning  injection,  87.7  c.c. 
Autopsy.  —  Weight    2326  grams!     The   peritoneal,   pleural,  and 
pericardial  cavities  are  dry.     The  kidneys  are  soft  and  bleed  a  normal 
amount.     A   few  pinpoint   haemorrhagic  spots  are  found   in   the 
bladder. 


44  NEPHRITIS 

2.  We  need  not,  however,  go  outside  of  the  body  in 
order  to  get  a  sufficient  amount  of  acid  to  so  upset  our 
neutrality  mechanism  in  the  kidney  as  to  lead  to  an  albumi- 
nuria. As  is  well  known,  large  amounts  of  acid  (especially 
lactic  acid)  are  produced  in  the  muscles  when  these  con- 
tract. If  the  muscle  works  under  physiological  conditions 
and  not  too  fast,  the  acid  as  formed  may  be  largely  oxidized 
in  situ.  But  if  the  muscle  works  more  rapidly  then  more 
acid  is  produced  than  can  be  oxidized  in  the  muscles  and 
so  in  the  higher  animals  some  passes  unchanged  into  the 
blood,  with  this  to  the  kidneys,  and  then  out  in  the  urine.  ^ 
It  is  evident  that  the  opportunities  for  such  an  accumula- 
tion of  acid  in  the  body  become  the  greater  the  more 
rapidly  and  the  harder  the  musculature  of  the  body  works, 
and  we  should  add,  the  more  defective  the  oxygen  supply 
to  the  working  muscles,  for  this  element  is  necessary  for 
the  proper  oxidation  of  the  acid  in  the  body.  Now  such  a 
combination  of  hard  work  with  a  (temporarily)  defective 
ox>^gen  supply  to  the  active  muscles  is  furnished  whenever 
the  organism  engages  in  exercise  that  calls  for  more  than 
usual  effort.  We  are  therefore  not  surprised  to  find  that 
soldiers  after  prolonged  marches,  women  in  labor,  Marathon 
runners,  etc.,  give  evidences  of  an  albuminuria  when  ex- 
amined after  such  exertions. ^  The  amount  of  exercise 
needed  to  bring  about  such  albuminurias  is  really  sur- 
prisingly low,  as  is  indicated  by  the  following: 

Experiment  i8.  —  Seven  trained  athletes  just  before  entering 
upon  a  game  of  basket  ball  were  asked  to  void  their  urine  into  a 
series  of  flasks.     At  the  end  of  the  game  which  lasted  one  and  a  half 

1  Trasahuro  Araki:  Zeitschr.  f.  physiol.  Chemie,  19,  422  (1894),  where  ref- 
erences to  his  eadier  papers  may  be  found;  Hoppc-Seylcr,  ibid  19,  476  (1894)- 
Fletcher  and  Hopkins,  Journal  of  Physiology,  35,  247  (1907). 

2  ir.  Leube:  Virchow's  Arch.,  72,  145  (1878);  G.  Edlefsen:  Centralbt.  f.  d. 
med.  Wissensch.,  762  (1879);  C.  von  Noorden:  Arch.  f.  klin.  Med.,  38,  205 
(1886). 


NEPHRITIS 


45 


hours  they  voided  their  urine  a  second  time  into  a  second  series  of 
flasks.  Heller's  test  was  then  applied  to  the  various  specimens  of 
urine.  While  none  of  the  players  showed  any  trace  of  albumin  in  his 
urine  before  the  play,  all  gave  strikingly  marked  reactions  after  the  game. 
The  results  of  the  tests  applied  to  the  urines  voided  after  the  game 
are  shown  in  Figs.  lo  and  ii.     The  first  four  tubes  are  photographed 


Fig.  io. 


Fig.  II. 


against  a  white  background,  the  three  of  Fig.  1 1  against  a  black.  The 
faint  albumin  ring  present  in  the  tube  on  the  extreme  right  of  Fig.  ii 
scarcely  shows  in  the  photograph.  Interestingly  enough,  this  specimen 
of  urine  came  from  a  player  who  was  in  the  game  but  five  minutes. 

Experiment  19.  —  Five  trained  athletes  shortly  before  engaging 
in  a  match  game  of  basket  ball  void  their  urine  into  a  series  of  flasks. 
All  the  urine  voided  during  the  succeeding  1 1  hours  during  which  the 
game  is  played  is  collected  in  a  parallel  series  of  flasks.  In  none  of 
the  control  urines  with  the  exception  of  that  of  Player  IV  are  there 
found  albumin  or  casts.  This  player  had  found  it  necessary  before 
coming  to  the  game  to  rush  about  town  making  train  and  street-car 
connections  and  had  moreover  had  a  "  cold  "  for  three  days  previ- 
ously. After  the  game  all  the  players  showed  an  albuminuria  and  a 
great  many  granular,  hyaline,  and  mixed  casts.  The  albumin  and  the 
casts  in  the  previously  affected  individual  were  markedly  increased. 
The  findings  are  illustrated  in  Fig.  12  and  in  the  appended  Table  III. 


46 


NEPHRITIS 


The  five  tubes  on  the  right  show  the  results  of  applying  the  cold 
nitric  acid  test  to  the  urine  after  the  game.  The  tube  on  the  extreme 
left  shows  the  albuminuria  existing  in  Player  IV  even  before  entering 
the  game.    The  quantitative  estimations  in  the  Eshach  tubes  were 


Fig.  12. 

carried  out  in  the  ordinary  way  using  Tsuchiya's^  phosphotungstic 

acid  reagent.      The  photograph  was  made  after  the  tubes  had  stood 

for  only  6  hours.     The  readings  in  the  table  were  made  after  24  hours. 

TABLE   III. 

Before  the  Game. 


Player 

Amount  of 
urine  in  cubic 
centimeters. 

Nitric  acid  test. 

Casts. 

I 

II 

III 

IV 
V 

60         ) 

158 
5        ) 

47 

134 

Negative 

Positive        < 
Negative 

None 

Occasional  granular 
and  hyaline 
None 

*  Tsuchiya:  Centralbl.  f.  inn.  Med.,  29,  105  (1908). 
Phosphotungstic  acid,  1.5  grams. 
Concentrated  hydrochloric  acid,  5.0  c.c. 
Alcohol  to  make,  loo.o  c.c. 


NEPHRITIS 
After  the  Game  (i|  Hour  Period). 


47 


Player. 

Amount  of 
urine  in 

cubic  centi- 
meters. 

Nitric  acid 
test. 

Casts. 

Esbach  reading 
with  phospho- 
tungstic  acid. 

Albumin 

excreted  in 

grams. 

I 

II 

III 

IV 
V 

i68 

69 

35 
30 
94 

Positive  -| 

Many   hyaline, 
granular,  and 
mixed     casts 
present  in  all. 

0.6 
325 
2.3 
50 

2.75 

O.III 
0.224 
0.080 
0.150 
0.258 

Av.  0.163 

A  remarkably  short  period  of  hard  athletic  work  suffices 
to  produce  a  great  albuminuria,  as  the  following  taken 
from  many  such  observations 
shows : 

Experiment  20.  —  B ,  a 

well-trained  and  expert  Uni- 
versity runner  ran  a  quarter- 
mile  race.  Before  starting  he 
voided  54  c.c.  of  urine  which  on 
examination  showed  no  albumin. 
After  his  race  (time:  58  seconds!) 
he  voided  59  c.c.  of  urine  in  which 
much  albumin  was  found.  In 
Fig.  13  are  shown  the  results  of 
the  albumin  tests  as  applied  to 
the  two  samples  of  urine.  In  the 
two  tubes  on  the  right  the  cold 
nitric  acid  test  has  been  applied 
to  the  urines;  in  the  tube  on  the 
left  a  quantitative  estimation  has 
been  carried  out  in  an  Esbach 
tube  with  Tsuchiya^s  phospho- 
tungstic  acid  reagent. 

3.  A  condition  in  the  body  entirely  analogous  to  that 
produced  voluntarily  by  the  athlete  in  his  athletic  activi- 
ties is  created  through  any  uncompensated  heart  lesion  or  any 
disease  of  the  lung  of  such  a  character  as  to  materially  inter- 
fere with  the  proper  aeration  of  the  blood.     Either  of  these 


Fig.  13. 


48  NEPHRITIS 

conditions  interferes  with  the  proper  escape  of  carbon 
dioxide  from  the  blood  (and  so  from  the  cells  in  which  this 
is  produced).^  But  they  do  more  than  this,  they  place  the 
organism  as  a  whole  in  a  state  of  lack  of  ox}^gen,  and  as  a 
necessary  consequence  of  this  we  know  from  the  studies  of 
Trasahuro  Araki,-  Hermann  Zillessen,^  and  P.  von  Terray^ 
that  we  get  an  abnormal  production  and  accumulation  of 
other  acids,  notably  lactic  and  oxalic  acids,  in  the  tis- 
sues. Heart  or  lung  lesions  therefore  are  potent  to  lead 
to  that  same  abnormally  high  acid  content  of  the  cells  of 
the  kidney  that  we  previously  found  created  through  the 
direct  injection  of  acids,  or  the  hard  work  of  the  athlete, 
and  so  we  are  prepared  to  find  in  these  pathological  states 
of  the  heart  and  lung  that  albuminuria  is  again  a  common 
consequence.  As  a  matter  of  fact  the  association  of 
^'  nephritis  "  or  ^'Bright' s  disease  "  with  heart  lesions  of 
the  most  varied  kinds,  or  pathological  conditions  in  the 
lung  (manual  compression  of  the  thorax,  pleurisy  with 
effusion)  that  reduce  its  ventilation  area  sufficiently,  is  so 
constantly  observed  that  it  is  taken  for  granted  clinically. 

4.  It  requires  no  special  comment  to  recognize  that  a 
whole  series  of  pathological  states  such  as  the  severer 
anaemias,  carbon  monoxide  poisoning,^  and  epileptic  seiz- 
ures, which  at  first  sight  seem  to  have  nothing  in  common 
with  each  other,  contain  within  themselves  all  the  elements 
necessary  for  the  development  of  an  albuminuria.  The 
severe  anaemias  (leukaemia  or  pernicious  anaemia)  merely 
constitute  further  ways  of  interfering  with  a  proper  oxygen 

1  Slrassburg:  Pfluger's  Arch.,  6,  94  (1873);  yl.  Ewald:  Arch.  f.  (Anat.  und) 
Physiol.,  663  (1873);  123  (1876). 

2  T.  Araki:  Zeitschr.  f.  physiol.  Chemie,  15,  335  and  546  (1891);  16,  453 
(1892);  17,  311  (1893);  19,  422  (1894). 

3  //.  Zillessen:  Zeitschr.  f.  physiol.  Chemie,  15,  387  (1891). 
*  P.  von  Terray:  Pfluger's  Arch.,  65,  393  (1896). 

5  G.  Thompson:  Trans.  Assoc.  Am.  Physicians,  1902;  William  Ravine:  Per- 
sonal Communication. 


NEPHRITIS  49 

supply  to  the  tissues.  Both  are  accompanied  by  an 
abnormal  storage  and  production  of  acid  in  the  tissues 
as  evidenced  by  Felix  Hoppe-Seyler's  ^  and  T.  Irasawa's  ^ 
chemical  analysis  of  the  urine,  and  R.  von  JakscKs  ^  titrations 
of  the  blood  in  cases  of  severe  anaemia.  An  abnormal  acid 
production  in  carbon  monoxide  poisoning  has  been  proved 
by  T.  Araki,^  E.  Munzer  and  P.  P alma ;^  in  epilepsy  (severe 
muscular  exertion  with  defective  breathing)  by  Araki  and 
E.  Mendel.  As  cHnicians  well  know,  the  existence  of  an 
albuminuria  in  any  of  these  pathological  states  is  usual. 

5.  The  aetiological  importance  of  "  cold  "  (in  the  strict 
sense  of  the  word  as  a  lowering  of  the  body  temperature 
and  unaccompanied  by  an  infection)  in  the  production  of 
an  acute  nephritis,  or  in  the  lighting  up  of  a  chronic  one 
that  has  slumbered  for  a  time,  has  always  been  insisted  upon 
by  the  older  observers.  This  view  finds  a  rigid  scientific 
support  in  our  present  knowledge  of  the  physiological 
effects  of  low  temperature  upon  the  warm-blooded  animals. 
Of  these  none  is  more  characteristic  than  the  rise  in  the 
acid  content  of  the  cells  of  an  animal  so  exposed.^    In  this 

^  F.  Hoppe-Seyler:  Zeitschr.  f.  physiol.  Chemie,  19,  473  (1894). 

2  T.  Irasawa:  Zeitschr.  f.  physiol.  Chemie,  15,  380  (1891). 

3  R.  von  Jaksch:  Klinische  Diagnostik,  Fiinfte  Aufl.  2.     Berlin,  1901. 
*  T.  Araki:  Zeitschr.  f.  physiol.  Chemie,  15,  335  (1891). 

^  E.  Miinzer  and  P.  Palma:  Prager  Zeitschr.  f.  Heilk,  15,  (1894). 

6  See  Araki:  Zeitschr.  f.  physiol.  Chemie,  16,  453  (1892).  On  the  basis 
of  this  same  acid  production  we  can  with  the  greatest  ease  explain  the  pre- 
cipitation of  an  attack  of  haemoglobinuria  in  the  cases  of  so-called  paroxys- 
mal hoemoglobinuria  when  these  patients  take  a  cold  bath,  are  exposed  to 
cold,  etc.  The  acid  produced  under  these  circumstances  rises  to  the  point 
where  it  leads  to  a  haemolysis  of  the  patient's  red  blood  corpuscles.  This 
view  is  supported  by  the  fact  that  it  is  possible  to  precipitate  an  attack  of 
haemoglobinuria  for  diagnostic  purposes  quite  as  easily  through  temporary 
obstruction  of  the  circulation  in  the  arm  by  applying  a  band  about  it  (ac- 
cumulation of  carbon  dioxide  and  production  of  other  acids  due  to  a  lack  of 
oxygen),  as  through  the  customary  immersion  of  the  extremities  in  cold 
water.  The  essential  nature  of  the  paroxysmal  haemoglobinurias  would 
seem  to  reside  in  the  lesser  resistance  which  the  red  blood  corpuscles  of  such 


50 


NEPHRITIS 


way  do  we  find  a  ready  explanation  of  why  such  trivial  ex- 
posure to  cold  as  is  produced  by  a  cold  bath  leads,  in  not  a 
few  individuals,  to  the  appearance  of  albumin  in  the  urine. 

6.  Thus  far  we  have  discussed  only  general  conditions  — 
conditions  affecting  the  whole  animal  —  that  are  capable  of 
inducing  an  abnormal  storage  or  production  of  acid  in  the 
body,  and  so  of  inducing  an  albuminuria.  We  will  now 
consider  a  series  of  more  local  conditions  that  bring  about 
the  same  result. 

Instead  of  interfering  with  the  normal  action  of  the  heart 
or  lungs  an  effective  state  of  lack  of  oxygen  in  the  kidney 
can,  of  course,  be  induced  by  direct  interference  with  the 
normal  blood  flow  through  this  organ  (see  Experiment  33). 
Experimentally  such  a  condition  is  easily  established  by  total 
or  partial  ligation  of  either  the  arterial  or  the  venous  blood 
supply  of  this  organ,  a  state  that  has  its  clinical  parallel 
in  such  affections  as  partial  or  complete  occlusion  of  the 
renal  vessels  through  arteriosclerosis,  thrombosis,  embolism, 
or  the  pressure  of  tumors,  etc.,  upon  these  vessels.  But  as 
the  experiments  of  T.  Araki  and  H.  Zillessen  have  shown 
such  an  interference  with  the  normal  blood  supply  (oxygen 
supply)  to  any  of  the  parenchymatous  organs  is  followed 
immediately  by  the  accumulation  of  acids  in  the  affected 
tissues.  Do  we  now  find  that  in  such  local  circulatory 
disturbances  of  the  kidney  we  get  an  albuminuria?  That 
we  do  is,  of  course,  known  to  everyone  —  it  constitutes, 
since  Max  Herrmann^ s  ^  experimental  studies,  one  of  the 

patients  have  to  such  a  haemolytic  agent  as  an  acid.  The  resistance  to 
such  a  hemolytic  agent  is  enormously  increased  by  the  addition  of  various 
salts  to  the  blood,  as  Oscar  Berghausen  has  sho\\Ti.  This  fact  is  not  only  of 
theoretical  interest,  as  I  have  tried  to  show  in  discussing  the  nature  of 
haemolysis  [Fischer:  KoUoid  Zeitschr.  5,  146  (1909)  or  (Edema,  166  (New 
York,  19 10)],  but  of  direct  therapeutic  use  in  the  treatment  of  these  cases  of 
haemoglobinuria  (diet  rich  in  alkahes,  administration  of  calcium  salts,  etc.). 
^  Max  Herrmann:  Sitzungsber.  d.  \\^iener  Acad.  Math.-phys.  Klasse, 
65,  (1861). 


NEPHRITIS  51 

classical  facts  of  pathological  physiology;  it  is  attested  to 
by  the  experience  of  any  medical  diagnostician ;  it  is  the  bug- 
bear of  surgeons  who  operate  on  the  kidney  and  find  a  tem- 
porary closure  of  the  renal  vessels  expedient  or  necessary.  ^ 
7.  Instead  of  interfering  directly  with  the  oxygen  supply 
to  the  kidney  by  procedures  which  interfere  with  the  blood 
supply  to  this  organ,  we  can  bring  about  the  same  result  in 
a  more  subtle  way  by  giving  the  kidney  parenchyma  its 
normal  oxygen  supply,  but  by  so  interfering  with  the 
chemistry  (enzymatic  processes)  of  the  cells  themselves 
that  make  up  the  kidney  as  to  render  these  incapable  of 
utilizing  in  proper  form  the  oxygen  that  is  freely  supplied 
them.  So  far  as  the  end  result  is  concerned,  it  matters 
little,  of  course,  whether  we  interfere  with  the  normal  oxida- 
tion, for  example,  of  the  carbohydrates  of  the  living  cell 
into  carbon  dioxide  and  water  by  shutting  off  the  oxygen 
supply  to  the  cell  and  so  halting  the  decomposition  of  the 
carbohydrates  when  these  have  been  changed  to  lactic, 
oxalic,  formic,  and  other  acids  (saccharinic  acids) ;  ^  or 
whether  we  do  nothing  about  the  oxygen  supply  but  intro- 
duce something  into  the  cell  which  prevents  the  oxidation 
of  the  lactic  acid  as  formed  to  carbon  dioxide  and  water 
(or  more  probably  the  mother  substance  of  the  lactic  acid 
glycerine  aldehyde).^    The  cells  of  the  living  body  in  the 

^  For  a  discussion  of  the  methods  to  be  employed  in  combating  the  evil 
consequences  of  such  temporary  closure  see  Part  IV  dealing  with  the  treat- 
ment of  nephritis. 

2  The  chemical  aspects  of  this  problem  of  the  formation  of  acids  from 
carbohydrates  in  the  absence  of  oxygen  are  discussed  by  Felix  Hoppe-Seyler: 
Berichte  d.  deut.  chem.  Gesellsch.  4,  346  (1871);  H.  Kiliani:  ibid,  15,  701 
(1882);  Diiclaux:  Compt.  rend.,  94,  169;  Schiitzenherger:  ibid,  76,  470; 
Buchner,  Meisenheimer,  and  Schade :  Berichte  d.  deut.  chem.  Gesellsch.,  39, 
4217  (1906);  /.  U.  Nef:  Liebig's  Annalen,  357,  214  (1907)-  The  biochem- 
ical aspects  of  this  same  problem  are  discussed  in  the  papers  on  lack  of 
oxygen  already  referred  to  on  pages  48  and  49. 

3  In  this  connection  see  the  interesting  work  of  R.  T.  Woodyait:  Journal 
of  the  American  Medical  Association,  65,  2109  (1910). 


52 


NEPHRITIS 


end  get  into  the  same  state  whether  they  have  their  oxygen 
supply  cut  off,  or  whether  this  is  not  interfered  with,  but 
they  are  ''  poisoned  "  in  such  a  way  as  to  be  unable  to 
utilize  this  oxygen  as  normally. 

As  has  been  shown  particularly  well  by  T.  Araki,  a  large 
number  of  poisons  lead  to  the  same  state  of  lack  of  oxygen, 
with  its  associated  abnormal  production  and  accumulation 
of  acids  in  the  tissues,  as  do  the  grosser  interferences  with 
the  oxygen  supply  to  the  various  organs  or  the  body  as  a 
whole,  that  have  already  been  described.  And  so  it  can- 
not surprise  us  to  discover  that  ArakVs  list  of  poisons  — 
poisons  utilized  to  show  that  an  abnonnal  acid  production  is 
the  constant  accompaniment  of  a  state  of  lack  of  oxygen  in  the 
tissues  no  matter  how  produced  —  is  identical  with  the  list  of 
poisons  familiar  to  any  laboratory  or  clinical  worker  who  has 
busied  himself  with  the  problem  of  the  toxic  nephritides: 
metallic  salts,  such  as  those  of  arsenic,  uranium,  chromium, 
and  lead;  alkaloids,  such  as  morphine,  cocaine,  and  strych- 
nine; anaesthetics,  such  as  alcohol,  ether,  and  chloroform; 
unclassified  poisons,  such  as  amyl  nitrite,  the  cyanides,  and 
phosphorus. 

8.  In  concluding  this  section  we  need  to  discuss  the 
albuminurias  encountered  in  three  conditions  which  not 
only  are  readily  interpretable  on  the  basis  of  our  conten- 
tion that  albuminuria  results  whenever  abnormally  great 
amounts  of  acid  accumulate  in  the  kidney  but  give  this 
contention  valuable  support. 

Since  Rudolph  Virchow^s  description  of  the  condition 
fifty  years  ago,  the  albuminuria  of  the  newborn  constitutes 
a  matter  of  common  knowledge  to  every  pasdiatrist.  It 
occurs  in  perfectly  healthy  infants  as  a  transitory  phenome- 
non, is  regarded  as  ''physiological,"  and  to  it  ordinarily  no 
clinical  importance  is  attached.  Whence  comes  it?  The 
condition  is  most  commonly  found  in  "  hard  '*  labors,  when 


NEPHRITIS  53 

the  cord  prolapses,  in  breech  presentations,  etc.,  all  of 
them  conditions  which  mean  a  state  of  more  than  the 
normal  lack  of  oxygen  in  the  organism  of  the  child  during 
the  process  of  its  birth.  Even  normal  labor  means  of 
course  a  decided  interference  with  the  circulation  of  the 
infant,  —  is  it  not  in  this  fact  and  the  associated  accumu- 
lation of  carbon  dioxide  and  other  acids  in  the  blood  that 
the  cause  of  the  first  respiration  is  to  be  sought,  as  Zuntz 
has  shown?  Difficult  labors  mean  in  to  to  only  a  more  than 
usual  interference  with  the  circulation  of  the  child.  It  is 
entirely  a  matter  of  definition  as  to  just  how  much  of  this 
we  will  accept  as  '^  physiological."  But  when  we  have  thus 
connected  the  development  of  the  albuminuria  with  a  dis- 
turbance in  the  general  circulation  of  the  child  then  we 
have  made  it,  at  the  same  time,  a  mere  subheading  of  the 
albuminurias  discussed  in  paragraph  3  of  this  section  (page 
47),  and  the  albuminuria  is  ''  physiological  "  only  as  we  will 
accept  little  or  great  interference  with  the  circulation  in  the 
infant  during  its  birth  as  "  physiological." 

Albuminuria  is  the  constant  accompaniment  of  salt  starva- 
tion, be  this  a  complete  salt  starvation  or  only  such  a  par- 
tial one  as  is  induced  by  ehminating  completely  the  sodium 
chloride  from  the  food.  Under  this  same  heading  is  to  be 
classed  the  albuminuria  consequent  upon  the  excessive  con- 
sumption of  water  low  in  salts.  The  latter  washes  the  salts 
out  of  the  body  (see  Section  4  of  Part  III)  and  so  leads 
indirectly  to  the  same  state  as  that  induced  by  a  lack  of 
salts  in  the  diet.  The  effect  of  a  salt-free  diet  is  twofold. 
In  the  first  place  it  leads  to  the  accumulation  of  acids  in  the 
tissues.^  Other  things  being  equal,  we  have  on  this  basis 
alone  therefore  a  reason  for  the  albumin  going  into  solution 
(and  so  an  albuminuria)  when  salts  are  withheld  from  the 

^G.  Bunge:  Zeitschr.  f.  Biol.,  10,  iii  (1874);  see  also  /.  Forster:  ibid,  9, 
297,  369  (1873);  N.  Lunin:  Zeitschr.  f.  physiol.  Chemie,  5,  31  (1881). 


54  NEPHRITIS 

diet.  But  the  salts  act  in  yet  another  way.  We  found,  in 
detailing  the  experiments  on  the  ^'  solution  "  of  fibrin  and  of 
gelatine  in  acids,  that  this  tendency  of  the  colloidal  gels  to 
go  into  solution  in  a  given  concentration  of  acid  is  greatly 
inhibited  through  the  presence  of  all  salts,  even  neutral  salts 
incapable  of  an  effect  that  might  be  construed  as  due  to  a 
mere  neutralization  of  the  acid.  Through  the  withdrawal 
of  salts  from  the  tissues,  whether  by  salt  starvation  or 
through  leaching  these  out  with  water,  we  favor  therefore 
the  tendency  of  the  proteins  to  go  into  solution  in  two  ways: 
not  only  do  we  render  possible  an  abnormal  production  or 
accumulation  of  acids  in  the  tissues,  but  we  take  away  at 
the  same  time  the  effect  of  the  salts  in  reducing  the  tend- 
ency of  the  colloids  to  go  into  solution  in  such  acids  as 
may  be  abnormally  present,  or  those  which,  like  carbon 
dioxide,  are  normally  produced  in  the  tissues. 

9.  If  now  albuminuria  represents  merely  that  simple 
** solution"  of  the  albumin  of  the  kidney  substance  itself 
in  the  urine,  or  if,  in  other  words,  it  does  not  come  from 
the  blood  (except  in  that  indirect  way  in  which  the  pro- 
teins of  any  cell  come  originally  from  the  blood),  then 
albuminuria  cannot  be  that  strange  and  specific  thing 
which  as  clinicians  we  are  likely  to  make  it.  Any  cell  must, 
under  conditions  similar  to  those  existing  in  the  cells  of  the 
kidney  when  this  is  nephritic,  be  capable  of  serving  as  a  source 
of  albumin  to  a  surrounding  liquid  medium,  a7id  so  be  capable 
of  being  responsible  for  a  state  which  in  the  kidney  goes  by  the 
name  of  ^'albuminuria.''  A  little  thought  will  show  that 
such  actually  is  the  case. 

Any  worker  in  the  biological  sciences  is  familiar  with  the 
ancient  fact  that  ''dead"  organisms,  be  these  unicellular 
or  multicellular,  allow  the  escape  of  albumin  from  them. 
A  frog  or  fish  living  in  his  aquarium  does  not  impart  an 
albumin  reaction  to  the  water  in  which  he  lives.     But  let 


NEPHRITIS  55 

him  die  and  in  a  few  hours  the  previously  clear  water  gives 
a  positive  result  when  tested  for  albumin,  and  this  reaction 
becomes  the  more  intense  as  time  goes  on.  What  happens 
is,  of  course,  that  after  death  the  tissues  become  acid  in 
reaction,  and  so  some  of  the  protein  now  goes  into  "solu- 
tion" in  the  surrounding  medium. 

But  we  need  not  wander  so  far  away  from  the  mammals, 
or  in  fact  the  living  animal  itself,  in  order  to  show  that 
''albuminuria"  is  not  the  specific  thing  we  think  it.  As 
surgeons  well  know,  the  normal  intestinal  juices  scarcely 
yield  an  albumin  test,  yet  the  fluid  contained  in  a  strangu- 
lated hernia  or  a  volvulus  is  rich  in  albumin.  Here  the 
interference  with  the  circulation  to  the  gut,  produced 
through  the  strangulation  or  the  twist,  has  placed  a  section 
of  the  bowel  in  a  state  of  lack  of  oxygen;  it  develops  in 
consequence  an  abnormally  high  acid  content,  and  so  some 
of  the  proteins  of  the  gut  wall  go  into  "solution"  —  in 
other  words,  we  get  in  the  bowel  what  in  the  kidney  is 
called  albuminuria. 

Analogous  conditions  exist  for  any  of  the  parenchym- 
atous organs.  When  any  organ  is  placed  under  conditions 
which  lead  to  an  increase  in  its  acid  content,  a  state  analo- 
gous to  the  albuminuria  of  the  kidney  results.  The  lymph 
coming  from  a  muscle  that  is  made  to  work  hard  has  a 
higher  albumin  content  than  that  coming  from  this  same 
muscle  when  at  rest,  and  when  the  circulation  through  the 
liver  is  impeded  (I  should  say  oxygen  supply  through  the 
hepatic  artery  is  interfered  with),  either  through  ligation  of 
the  inferior  vena  cava  or  obturation  of  the  thoracic  aorta, 
the  albumin  content  of  the  lymph  coming  from  this  organ 
begins  to  rise  as  E.  H.  Starling'^  has  clearly  shown. 

*£.  H.  Starling:  Jour,  of  Physiology,  16,  224  (1894);  17,  30  (1895);  see 
also  Bayliss  and  Starling:  ibid,  16,  159  (1894). 


56  NEPHRITIS 

11.   THE    ^MORPHOLOGICAL    CHANGES    IN    THE 
KIDNEY. 

I.   Introduction. 

Anyone  who  has  on  the  one  hand  busied  himself  with 
the  clinical,  or  as  we  might  better  say,  the  biochemical, 
aspects  of  nephritis,  on  the  other  wdth  the  morphological 
aspects  of  this  same  problem,  as  this  has  been  developed  for 
us  during  the  last  two  or  three  decades,  must  be  struck 
not  alone  by  the  fact  that  the  two  have  grown  up  practi- 
cally independently  of  each  other,  but  that  they  have  made 
but  slight  effort  to  find  common  ground. 

As  a  matter  of  fact,  w^hen  we  attempt  to  fiind  a  con- 
nection between  the  comparatively  simple  biochemical 
characteristics  of  nephritis  and  the  elaborate  morphological 
analyses  of  the  organs  from  patients  who  have  clinically 
shown  the  biochemical  marks  of  a  nephritis,  this  is  at  first 
sight  not  easy.  Even  if  we  ignore  the  fact  that  much  of 
that  which  is  supposed  to  characterize  nephritis  morpho- 
logically has  nothing  to  do  with  the  albuminuria,  the 
changes  in  the  secretion  of  water,  the  changes  in  the  secre- 
tion of  dissolved  substances,  etc.,  which  are  the  distinguish- 
ing marks  of  a  nephritis  biochemically,  there  still  remains 
an  apparent  lack  of  connection  between  the  facts,  to  which 
any  clinician  or  pathologist  will  testify,  namely,  that  indi- 
viduals may  die  of  an  acute  Brighfs  disease  and  show  sur- 
prisingly little  macroscopic  or  microscopic  change  in  the 
kidney,  while  others,  never  affected  with  any  symptoms 
referable  to  the  urinary  system,  may  show  on  autopsy  the 
infant-sized  kidneys  of  chronic  interstitial  nephritis.  And 
yet  if  we  will  but  free  our  minds  from  the  erroneous  con- 
clusions to  which  the  temptations  of  elaborate  fixing  and 
staining  methods  and  high  power  microscopes  have  led  us, 


NEPHRITIS  57 

it  is  an  easy  matter  to  see  that  all  the  morphological 
changes  that  occur  in  a  kidney,  the  seat  of  an  acute  or 
chronic  nephritis,  are  fundamentally  simple  in  character, 
and  that  they  are  easily  brought  into  connection  with  the 
clinical  manifestations  of  the  disease.  We  will  discover  at 
the  same  time  that  the  essential  morphological  changes  of 
acute  and  chronic  nephritis  were  recognized  and  a  satis- 
factory classification  of  the  nephritides  on  morphological 
grounds  was  made  decades  ago,  more  especially  by  Weigert,^ 
and  that  a  classification  of  the  nephritides  on  the  basis  of 
pathological  physiology  brings  us  in  'these  modern  days 
back  to  yet  older  teachings,  to  those  of  Frerichs^  for 
example,  who  regarded  all  the  nephritides  to  be  in  essence 
the  same. 

The  morphological  changes  that  occur  in  the  kidney, 
which  any  pathologist  will  accept  as  characteristic  of  the 
acute  forms  of  nephritis,  and  for  the  recognition  of  which 
no  elaborate  histological  technique  is  at  all  necessary,  are : 

1.  An  increase  in  the  size  of  the  kidney,  traceable  on  the 
examination  of  fresh,  unfixed,  and  unstained  cells,  back  to 
an  increase  in  the  size  of  the  individual  cells  and  tissues 
composing  the  kidney. 

2 .  A  loss  of  the  normal  color  of  parts  or  all  of  the  kidney 
which  assume  a  less  gHstening,  drier,  and  more  opaque 
(boiled)  look.  On  microscopic  examination  this  change  is 
found  to  be  associated  with  the  appearance  of  granular 
substances  in  the  cells  of  the  affected  portions  of  the  kidney. 
This  change  in  color,  taken  in  conjunction  with  the  increase 
in  the  size  of  the  kidney,  constitutes  the  *' cloudy  swelling" 
of  the  pathologists. 

3.  The  appearance  of  blood  corpuscles  extra vascularly. 

1  The  most  accessible  of  Weigert's  papers  on  nephritis  appear  in  Virchow's 
Archiv  during  the  years  i860  to  1875. 

*  Frerichs:  Die  Bright'sche  Nierenkrankheit.  Braunschweig,  185 1. 


58  NEPHRITIS 

They  may  be  found  in  the  tissues  of  the  kidney  itself,  or  in 
the  spaces  about  the  glomerular  tufts  and  in  the  urinifer- 
ous  tubules. 

4.  Evidences  of  a  falling  apart  of  the  kidney  as  a  whole 
and  of  a  disintegration  of  the  indi\idual  cells  of  the  kidney. 
Under  this  heading  are  grouped  not  only  the  gross  destruc- 
tive lesions  observed  in  the  kidney,  such  as  the  rupture  of 
capillary  tufts,  but  the  separation  of  individual  and  groups 
of  cells  from  their  attachments  in  the  glomeruli,  Bowman^s 
capsule  and  the  uriniferous  tubules  (formation  of  casts). 

This  catalogue  of  morphological  changes  as  given  for  acute 
nephritis,  or  as  we  might  better  call  it  acute  parenchym- 
atous nephritis,  holds  with  but  small  modification  for  the 
chronic  parenchymatous  forms  also.  The  chronic  forms 
show  all  the  changes  of  the  acute  with  certain  others  added 
to  them,  notably  a  ''fatty  degeneration,"  and  the  develop- 
ment of  a  certain  amount  of  scar  tissue.  But  where  are  we 
to  put  the  chronic  interstitial  type  of  nephritis? 


2.   The  Relation  Morphologically  of  the  So-called  Chronic 
Interstitial  Nephritis  to  the  Parenchymatous  Tjrpes. 

The  most  apparent  difference  between  the  parenchyma- 
tous forms  of  nephritis  and  the  chronic  interstitial  resides 
in  the  difference  in  the  comparative  sizes  of  the  organs  as 
a  whole  in  the  two  conditions.  While  the  former  is  larger 
than  normal,  the  latter  is  smaller.  And  yet  this  does  not 
constitute  the  most  characteristic  difference  between  the 
two.  This  is  rather  to  be  sought  in  the  way  in  which 
the  two  pathological  states  are  brought  about. 

In  the  frankly  parenchymatous  forms  of  nephritis  the 
whole  kidney  is  usually  affected  at  once  and,  on  the  whole, 
equally.  If  the  kidney  cells  are  sufficiently  damaged,  and  the 
patient  dies,  we  find  on  autopsy  the  familiar  large  kidney. 


NEPHRITIS  59 

In  chronic  interstitial  nephritis  the  ultimate  picture  is  pro- 
duced through  a  gradual  but  complete  destruction  of  one 
piece  after  another  of  the  kidney  parenchyma,  with  re- 
placement of  the  defect  with  connective  tissue.  The  por- 
tions of  kidney  involved  in  this  localized  destruction  of  kidney 
parenchyma  show  all  the  signs  characteristic  of  parenchym- 
atous nephritis.  Between  these  localized  areas  of  paren- 
chymatous nephritis  the  kidney  tissue  is  healthy.  When, 
now,  we  remember  that  less  than  one-third  of  the  total 
kidney  substance  is  necessary  for  the  maintenance  of  life, 
it  is  easy  to  see  why  a  patient  with  chronic  interstitial 
nephritis  runs  along  in  a  fairly  normal  way.  The  de- 
struction of  the  kidney  occurs  so  very  slowly  that  little 
albumin  appears  in  the  urine,  and  casts  only  in  small  num- 
bers. So  the  patient  may  die  without  his  kidney  state 
ever  having  been  recognized,  or  the  symptoms  of  intoxi- 
cation characteristic  of  removal  of  kidney  substance  down 
to  the  physiological  minimum  may  be  the  first  to  draw 
our  attention  to  the  pathological  state,  clinically. 

We  shall  have  occasion  to  return  to  all  this  later.  For 
the  present  it  is  sufficient  to  merely  emphasize  the  fact 
that  a  chronic  interstitial  nephritis  is  in  essence  also  a  paren- 
chymatous nephritis,  —  a  slow-going  hut  progressive  localized 
parenchymatous  nephritis  resulting  in  death  and  loss  of  the 
involved  portions  of  the  kidney,  and  resulting  ultimately  in  a 
picture  which  is  best  described  by  calling  it  an  atrophy  of  the 
kidney.  The  patient  with  chronic  interstitial  nephritis  is, 
therefore,  in  the  same  position  as  an  animal  that  has  had 
its  kidney  substance  progressively  diminished  in  amount 
by  successive  operations  and  ablations  of  kidney  paren- 
chyma. The  man  who  has  gone  through  Kfe  without  signs 
or  symptoms  of  kidney  disease,  who  dies  of  other  causes 
than  kidney  disease  and  shows  on  the  autopsy  table  what, 
as  morpholo gists,  we  call  chronic  inters titi?l  nephritis,  is 


6o  NEPHRITIS 

simply  like  the  animal  that  has  suffered  a  great  reduction 
in  total  kidney  substance,  but  has  not  yet  reached  the 
physiological  minimum  compatible  with  life  for  that  animal 
under  the  conditions  under  which  it  has  to  live.  What  is 
left  of  kidney  parenchyma  to  man  or  animal  is  still  physi- 
ologically active  and  physiologically  adequate.  Such  a 
biological  contention  finds  its  morphological  support  in 
the  fact  that  the  parench}Tna  of  such  (morphologically) 
chronic  interstitial  t}^es  of  nephritis  shows  little  or  no 
change  either  macroscopically  or  microscopically  (''small 
red  kidney").  The  presence  of  the  connective  tissue  in 
the  kidney  is  an  accident,  it  is  scar  tissue,  and  whatever 
importance  we  may  care  to  attach  to  it  morphologically, 
this  is  no  more  any  indication  of  the  physiological  state  of 
the  kidney  parench}Tna  that  is  left  than  the  scar  which  re- 
pairs and  serves  to  reunite  the  ruptured  ends  of  a  muscle 
is  any  index  of  the  physiological  efficiency  of  that  muscle. 

With  this  we  have  disposed  of  the  apparent  difference  be- 
tween parenchymatous  nephritis  and  what  is  called  chronic 
interstitial  nephritis  so  far  as  differences  in  the  sizes  of 
the  kidney  as  a  whole  are  concerned.  At  the  same  time 
we  ha\'e  indicated  why  what  parenchyma  is  left  in  the 
(morphologically)  chronic  interstitial  nephritis  may  look 
fairly  normal  both  macroscopically  and  microscopically. 
Not  until  larger  portions  of  the  kidney,  or  maybe  all  that  is 
left  of  the  organ,  shows  the  changes  characteristic  of  the  paren- 
chymatous types  of  nephritis  {^^  small  gray  kidney  ^^),  do  we 
have  added  to  the  morphological  picture  of  chronic  interstitial 
nephritis,  as  already  described,  the  increase  in  the  size  and 
changes  in  the  color  of  the  individual  cells  of  the  kidney,  and 
franker  evidence  of  albumin,  blood,  and  casts  in  the  urine, 
as  listed  above,  vn  discussing  the  parenchymatous  types  of 
nephritis. 

In  thus  getting  the  chronic  interstitial  forms  of  nephritis 


NEPHRITIS  6l 

back  into  a  group  with  the  frankly  parenchymatous  forms, 
one  point  remains  undiscussed,  and  that  is  the  association 
of  an  oedema  and  a  diminished  secretion  of  urine  with  the 
one  form,  while  a  lack  of  oedema  and  an  (so-called)  increased 
urinary  output  go  with  the  other.  But  these  physiological 
phenomena  can  also  be  easily  explained,  as  will  be  done 
later. 

Let  us  now  discuss  the  morphological  changes  observed 
in  the  nephritic  kidney  as  listed  above,  seriatim. 

3.   The  Changes  in  the  Size  and  in  the  Color  of  the  Kidney 
in  Nephritis  (Cloudy  Swelling).^ 

§1. 

While  we  shall  later  find  ourselves  compelled  to  discuss 
these  two  changes  in  the  kidney  separately,  we  will  first 
take  them  up  together  because  it  is  in  this  form,  under  the 
caption  of  cloudy  swelling,  that  they  have  been  chiefly 
discussed  by  the  pathologists. 

As  is  familiarly  known,  we  are  indebted  to  Rudolph 
Virchow  not  alone  for  a  first  clean-cut  description  of  this 
cloudy  swelling  as  it  occurs  in  the  kidney  (and  other 
parenchymatous  organs) ,  but  for  a  first  attempt  to  analyze 
its  nature.  Virchow  held  cloudy  swelling  to  be  ''  a  kind 
of  acute  hypertrophy  with  tendency  to  degeneration,"  a 
phrase  which  has  found  its  way  into  even  our  most  mxodern 
textbooks  of  pathology.  But  while  such  a  phrase  still 
serves  many  as  a  satisfactory  characterization  of  the 
condition  from  a  biological  standpoint,  it  means  nothing, 
of  course,  from  the  standpoint  of  its  physicochemical 
analysis.  Toward  the  physicochemical  analysis  of  cloudy 
sweUing  Virchow  contributed  the  important  suggestion 
that  the  cause  of  the  granule  formation  in  the  cells  is  due 

^Martin  H.  Fischer:  Kolloid  Zeitschr.,  8,  159  (191 1). 


62  NEPHRITIS 

to  a  change  in  their  albun^inous  constitution.  He  based 
this  conchision  upon  the  fact  that  the  granules  are  soluble 
in  acids  and  alkalies,  and  not  in  ether,  thereby  distin- 
guishing them  from  fat  deposits  in  the  cells  (fatty  degenera- 
tion) which  at  times  mimic  in  general  appearance  cells 
affected  with  cloudy  sweUing.  For  the  increase  in  the  size 
of  the  cells  Virchow  gave  only  the  biological  explanation  of 
an  ''increased  irritation  "  of  the  affected  cells,  caused  for 
example  by  the  products  of  an  infectious  disease,  in  conse- 
quence of  which  they  were  made  to  take  up  ''  excessive 
amounts  of  nutrient  material." 

That  cloudy  swelhng  represents  a  change  in  the  albumi- 
nous constitution  of  the  cell  seems  never  to  have  been 
questioned.  Eduard  Rindfleisch  ^  accepted  this  belief  and, 
m.oreover,  expressed  himself  of  the  opinion  that  cloudy 
swelling  was  ''  passive  "  in  its  nature  and  due  to  ''  a  kind 
of  corrosive  action  in  consequence  of  which  the  albuminous 
matters,  held  in  solution  by  the  protoplasm,  undergo 
coagulation  and  become  visible  as  minute  granules."  In 
1882,  Julius  Cohnheim  ^  subjected  Virchow^ s  teachings  to  a 
rigorous  critique.  That  the  process  of  cloudy  swelHng  in- 
volved the  albuminous  constituents  of  the  cell  he  did  not 
question,  but  he  perpetuated  a  conclusion  (erroneous  as  we 
shall  see)  of  Virchow^  when  he  wrote,  "Of  course  we  must 
deal  here  with  a  protein  that  is  different  from  that  which 
is  normally  present  in  the  cell  protoplasm  ...  as  we 
could  not  otherwise  account  for  the  optical  difference." 
But  Cohnheim,  too,  expressed  the  possibility  of  cloudy 
swelling  representing  ''  a  spontaneous  precipitation  in  solid 
form,  or  the  coagulation  of  a  previously  fluid  protein." 

^  Eduard  Rindfleisch:  Pathological  Histology.  Translated  by  Baxter,  30. 
London,  1872. 

2  Julius  Cohnheim:  Allgemeine  Pathologic,  Zweite  Auflage  1,  662;  2,  570. 
Berlin,  1882. 


NEPHRITIS  63 

What  underlies  such  a  change  in  the  albuminous  consti- 
tution of  the  cell,  he  did  not  attempt  to  say,  but  he  showed 
very  conclusively  that  the  causes  proposed  by  older  writers 
were  questionable  if  not  entirely  inadequate.  Thus  he 
showed  that  the  fever  accompanying  the  various  infections 
liable  to  be  accompanied  by  a  cloudy  swelling  could  not 
by  itself  be  the  cause  of  the  change,  by  calHng  attention  to 
the  well-known  fact  that  cloudy  swelling  may  be  absent  in 
cases  that  have  run  a  high  fever,  or  present  in  conditions 
not  associated  with  an  abnormal  rise  in  temperature. 

In  such  a  half-hypothetical  state  did  the  subject  of 
cloudy  swelling  remain  until  1901,  for  in  spite  of  various 
discussions  of  the  subject,  no  clear-cut  advajice  was  made 
either  toward  defining  more  precisely  what  cloudy  swelling 
is,  nor  yet  in  discovering  a  something  common  to  all  con- 
ditions associated  with  cloudy  swelling,  which  might  justly 
be  regarded  as  its  fundamental  ''  cause."  At  this  time 
H.  J.  Hamburger  ^  reported  a  series  of  observations  on  iso- 
lated liver,  kidney,  and  spleen  cells  which  served  to  establish 
more  firmly  what  can  justly  be  regarded  as  little  more  than 
lucky  speculation  on  the  part  of  the  older  writers.  Ham- 
burger applied  to  these  cells  some  earlier  observations  made 
on  red  and  white  blood  corpuscles.  In  a  study  of  the 
latter  he  had  found  that  various  acids,  including  carbon 
dioxide,  bring  about  an  exchange  of  substances,  including 
water,  between  the  red  and  white  blood  corpuscles  and  the 
serum  in  which  they  are  contained.  Under  the  influence 
of  acids  all  these  cells  take  up  water  from  their  surround- 
ings. He  paralleled  this  with  the  findings  of  previous  ob- 
servers that,  in  fevers  of  the  most  varied  origins,  acids  are 
produced  and  the  '^ alkalinity"  of  the  blood  is  reduced,  and 

^H.  J.  Hamburger:  Osmotischer  Druck  und  lonenlehre,  3,  49  (Wies- 
baden, 1904),  where  references  to  his  earher  articles  may  be  found.  See  also 
Karl  Landsteiner:  Ziegler's  Beitrage,  33,  237  (1903). 


64  NEPHRITIS 

so  concluded  that  in  this  acid  production  resided  the  cause 
for  the  enlargement  of  the  cells  in  cloudy  swelling.  Just  why 
acids  bring  about  any  enlargement  he  does  not  state  defi- 
nitely, though  changes  leading  in  the  aggregate  to  an  in- 
crease in  the  osmotic  pressure  of  the  cell  contents  are  held 
mainly  responsible.  Hamburger  then  points  out  that  the 
white  opaque  appearance  of  isolated  kidney,  liver,  and  spleen 
cells  exposed  to  dilute  acids  is  identical  with  that  of  cells 
affected  with  cloudy  swelling  and  discovered  post  mortem. 
Cells  treated  with  an  acid  are  studded  with  granules,  as 
are  the  cells  showing  a  cloudy  swelling  that  are  found  post 
mortem,  and  to  prove  that  the  granules  are  similar  in 
character  in  both,  and  represent  albumin  precipitates,  he 
calls  attention  to  the  fact  that  the  granules  which  he  has 
made  appear  through  a  weak  acid  dissolve  again  as  the 
acid  concentration  is  increased.  An  analogue  of  the  pro- 
duction of  the  granules  in  the  isolated  parenchyma  cells 
Hamburger  found  in  the  precipitation  of  albumin  from  a 
diluted  blood  serum  when  an  acid  is  added  to  this. 

The  first  great  value  of  Hamburger^ s  studies  resides  in  the 
fact  that  he  has  detailed  experiments  which  show  that  all 
the  necessary  elements  for  cloudy  swelling  reside  in  the 
parenchyma  cells  themselves,  and  that  he  has  pointed  out 
that  what  is  added  through  an  infectious  disease  (or  as  we 
might  say  in  order  to  make  our  contention  more  pointed, 
any  condition  which  is  capable  of  inducing  a  nephritis) 
may  be  nothing  more  than  a  Uttle  acid.  This  simple  reason- 
ing of  Hafuburger  does  away  with  the  biological  terminol- 
ogy that  has  so  long  been  appHed  to  the  subject  of  cloudy 
swelling,  and  renders  possible  an  attack  upon  the  problem 
in  the  Hght  of  the  simpler  concepts  of  physics  and  chemistry. 

Since  Hamburger^s  work  I  know  of  no  contributions  to 
the  subject  of  cloudy  swelling  which  have  either  ques- 
tioned the  correctness  of  his  view,  that  the  increased  ab- 


NEPHRITIS  65 

sorption  of  water  by  the  cell  affected  with  cloudy  swelling 
represents  an  osmotic  phenomenon,  nor  yet  any  which  have 
adduced  further  evidence  in  support  of  the  protein  precipi- 
tation idea  of  the  granule  formation  in  this  condition.  As 
the  subject  is  intimately  connected  with  our  problem  of 
the  morphological  changes  occurring  in  nephritis,  I  felt 
that  it  could  to  advantage  be  restudied  at  this  time,  es- 
pecially since  the  acquisitions  of  colloid  chemistry  —  the 
chemistry  of  the  very  substances  of  which  the  kidney  is 
composed  —  have  furnished  us  with  data  and  theoretical 
deductions  that  are  of  immediate  applicability  in  the 
analysis  of  this  problem.  By  utilizing  these  we  shall  find 
ourselves  in  a  position  to  give  a  simpler  physicochemical 
explanation  for  the  increased  water  absorption  by  the 
tissues  in  cloudy  swelling  than  is  contained  in  the  unsatis- 
factory osmotic  explanation  of  this  part  of  the  phenomenon, 
and  at  the  same  time  we  shall  learn  how  the  clouding  of  the 
parenchymatous  organs  follows  the  same  laws  as  the  pre- 
cipitation of  such  a  simple  colloid  as  casein.  In  this  way 
we  shall  find  a  ready  explanation  of  the  first  two  of  the 
morphological  changes  in  the  kidney  catalogued  above  and 
characteristic  of  nephritis,  namely,  the  increase  in  the  size 
of  the  parenchymatous  elements,  and  their  change  in  color. 
At  the  same  time  we  shall  find  that  both  arise  from  the 
same  abnormal  production  and  accumulation  of  acid  in 
the  kidney,  —  the  same  condition  therefore  that  we  have 
previously  held  responsible  for  the  albuminuria. 

§  2. 
We  shall  first  describe  a  series  of  observations  on  the 
artificial  production  in  excised  kidneys  of  the  changes 
characteristic  of  nephritis  (production  of  cloudy  swelling) 
which  will  prove  themselves  of  service  in  the  further 
analysis  of  our  problem.    The  methods  employed  in  these 


66  NEPHRITIS 

experiments  were  the  same  throughout.  The  kidneys  of 
healthy,  freshly-killed  rabbits  and  guinea  pigs  were  used, 
which  after  being  sliced  were  distributed  into  bowls  each 
containing  loo  ex.  of  the  necessary  solutions.  As  it  is  im- 
possible to  give  absolute  values  to  the  various  grades  of 
grayness  and  opacity  observed  in  the  different  solutions, 
one  can,  in  the  description  of  the  findings,  only  compare  the 
appearance  of  a  tissue  in  one  solution  with  that  of  a  similar 
piece  in  a  different  solution  at  the  same  time.  The  general 
conclusions  from  a  long  series  of  experiments  may  be  sum- 
marized as  follows: 

(a)  When  slices  of  fresh  kidney  are  dropped  into  dis- 
tilled water  they  slowly  swell  and  at  the  same  time  become 
gray.  A  tone  of  gray  that  is  readily  distinguishable  from 
the  color  of  the  normal  organ  appears  over  the  cut  surface 
some  three  or  four  hours  after  being  dropped  into  the 
water.  This  gradually  increases  in  intensity  until,  twenty- 
four  hours  after  the  beginning  of  the  experiment,  the  tissues 
look  decidedly  gray.  For  a  day  or  two  longer  this  may 
continue  to  increase  in  intensity,  but  the  change  from  the 
first  twenty-four  hours  is  not  very  marked.  As  the  tissue 
becomes  gray  it  shows  an  acid  reaction  to  litmus,  and  this 
acid  production  in  even  a  small  piece  of  tissue  may  be 
sufficiently  great  to  impart  an  acid  reaction  to  the  sur- 
rounding fluid. 

{h)  The  pieces  of  tissue  swell  much  more  rapidly  if  they 
are  placed  in  any  dilute  acid  instead  of  in  distilled  water. 
This  is  shown  in  Fig.  14.  A  has  sunply  been  protected 
against  evaporation.  B  has  lain  for  an  hour  and  a  half 
in  a  0.003  normal  hydrochloric  acid  solution.  The  two 
pictures  represent  opposite  faces  of  the  same  cut  through 
the  kidney.  The  tissues  also  become  gray  sooner  in  an 
acid  solution  than  in  distilled  water.  In  0.005  normal 
solutions  of  lactic,  formic,  acetic,   tartaric,  hydrochloric, 


NEPHRITIS  67 

sulphuric,  or  nitric  acids  a  decided  cloudiness  is  visible  in 
ten  minutes  after  immersion.  This  cloudiness  becomes 
gradually  more  marked.  After  three  hours,  when  the  con- 
trol in  distilled  water  is  just  showing  a  grayness,  the  sHces 
of  tissue  in  the  dilute  acids  are  grayer  than  the  controls 
appear  the  following  day.  The  various  acids  show  some 
difference  in  the  intensity  of  the  cloudiness  that  they  pro- 
duce, but  this  is  so  much  a  function  of  their  concentration 


Fig.  14. 

and  the  time  that  a  table  of  their  relative  effectiveness 
cannot  be  given  to  advantage.  After  another  two  hours 
the  tissues  in  all  the  acid  solutions  are  intensely  gray.  The 
control  in  pure  water  is  about  as  gray  as  the  tissues 
placed  in  the  dilute  acids  were  after  ten  minutes  of  immer- 
sion. On  the  following  day  an  ultimate  degree  of  grayness 
(a  typical  "boiled"  appearance)  is  shown  by  all  the  organs 
in  the  dilute  acids. 

Speaking  generally,  it  may  be  said  that  when  the  effects 
of  different  concentrations  of  the  same  acid  are  compared, 
the  cloudiness  develops  the  more  rapidly  the  greater  the 
concentration  of  the  acid.     So  far  as  intensity  is  concerned 


68  NEPHRITIS 

there  is,  however,  Httle  difference.  In  the  end  every  acid 
gives  the  tissues  a  boiled  appearance.  With  different 
concentrations  of  nitric  acid  I  found  the  boiled  appear- 
ance after  a  ten -minute  immersion  in  o.i  normal  acid. 
In  0.05  normal  acid  the  same  appearance  was  attained 
in  an  hour;  in  0.025,  o.oi,  and  0.002  normal  in  two  to 
three  hours. 

What  has  been  said  of  nitric  acid  holds  true  in  general 
for  all  acids,  though  there  are  more  or  less  specific  differ- 
ences with  the  different  acids  both  so  far  as  rapidity  of  de- 
velopment and  intensity  of  the  cloudy  sweUing  is  concerned. 
Acetic  acid  is  particularly  interesting.  With  increasing 
concentrations  of  the  acid  there  is  first  an  increase  in  the 
rate  and  (in  units  of  tim.e)  in  the  intensity  of  the  cloudiness 
produced.  If  we  observe  closely,  this  is  seen  to  be  followed 
with  increasing  concentrations  of  acid  (above  o.i  normal 
acetic  acid)  by  a  stage  in  which  the  cloudiness  is  less  than 
in  lower  concentrations.  To  see  these  successive  changes 
one  must  observe  especially  the  superficial  portions  of  the 
tissues.  A  second  clouding  can  now^  be  obtained  by  chang- 
ing to  one  of  the  ''strong"  acids  (nitric,  sulphuric,  or 
hydrochloric)  of  the  same  or  of  a  higher  normality  than 
that  of  the  acetic  acid  which  has  brought  about  the  dis- 
appearance of  the  first  clouding.  This  change  from  cloud- 
iness to  clearness  and  back  again  to  cloudiness,  with 
progressive  increase  in  the  concentration  of  an  acid,  can 
be  followed  particularly  well  under  the  rricroscope  [see  {g) 
below].  But  even  in  the  sections  of  tissue  kept  in  the 
"  stronger  "  acids  can  two  such  regions  of  cloudiness  sep- 
arated by  one  of  clearness  be  discerned.  I  found,  for  ex- 
ample, that  the  marked  cloudiness  of  slices  of  kidney, 
which  had  been  kept  for  one  and  one-half  hours  in  concen- 
trations of  nitric  acid  up  to  0.005  normal,  disappeared  when 
the  surface  of  the  organ  was  touched  with  the  ordinary 


NEPHRITIS  69 

weak  acetic  acid  of  our  laboratory  reagents,  to  reappear 
when  dilute  nitric  acid  was  substituted  for  it. 

The  cloudiness  of  the  tissues  obtained  in  any  of  the  acids 
listed  above,  if  developed  in  not  too  high  concentrations 
(below  0.005  normal),  can  also  be  made  to  disappear  if  the 
tissues  are  placed  in  equinormal  alkali  solutions,  or  in  alkali 
solutions  of  a  higher  concentration. 

{c)  Through  the  addition  of  various  salts  the  develop- 
ment of  a  cloudiness  in  any  acid  solution  can  be  either  re- 
tarded or  hastened.  So  far  as  the  absorption  of  water  is 
concerned,  all  the  salts  have  but  one  effect  —  they  decrease 
the  amount  of  the  swelling  in  the  acid  solution.  When  to  a 
0.005  normal  hydrochloric  acid  solution  enough  of  various 
potassium  salts  is  added  to  make  their  final  concentration 
0.05  molecular,  the  following  is  noted.  After  ten  minutes 
immersion  it  is  plainly  evident  that  some  of  the  salts  are 
accelerating  the  effect  of  the  acid  in  producing  the  devel- 
opment of  the  cloudiness,  while  others  are  inhibiting  it. 
In  an  hour  the  differences  are  very  marked.  The  sul- 
phocyanate,  iodide,  bromide,  and  nitrate  all  increase  the 
cloudiness,  the  first  named  being  the  most  powerful  in  this 
respect.  Then  comes  the  pure  acid.  Following  this  comes 
the  chloride,  the  acetate,  the  tartrate,  and  the  citrate. 
After  three  to  six  hours  of  immersion  the  differences  are 
still  more  striking.  In  the  solutions  containing  the  first- 
mentioned  salts  the  tissues  are  ^'boiled"  in  appearance. 
In  the  pure  acid  the  grayness  is  well  marked.  The  tissues 
in  the  solutions  containing  the  chloride  and  the  acetate  lag 
somewhat  behind  the  pure  acid.  In  the  tartrate  a  faint 
film  is  only  just  visible  over  the  surfaces  of  the  organs. 
The  sections  in  the  solutions  containing  the  citrate  look 
perfectly  normal.  In  fact,  in  the  two  last-named  solutions 
the  organs  retain  an  almost  normal  appearance  for  two  to 
three  days. 


70  NEPHRITIS 

Similar  results  are  obtainable  by  using  sodium  or  ammo- 
nium salts  in  place  of  the  potassium  salts,  or  lactic,  formic, 
or  m'tric  acid  in  place  of  the  hydrochloric,  except  that  in 
the  latter  case  the  absolute  rates  at  which  any  degree  of 
cloudiness  is  obtained  is  not  quite  the  same  as  in  hydro- 
chloric acid. 

{d)  Various  salts  accelerate  or  retard  the  development 
of  a  cloudiness  in  sections  of  kidney  placed  in  their  pure 
solutions,  in  just  the  same  way  as  they  accelerate  or  re- 
tard the  development  of  a  cloudiness  if  an  acid  is  added  at 
the  same  time,  only  the  rate  of  development  and  the 
absolute  intensity  of  the  cloudiness  attained  is  less  in  the 
pure  salt  solutions  than  in  mixtures  of  these  with  any 
acid.  In  all  salt  solutions  the  kidney  slices  swell  less  than 
in  pure  water.  These  findings  are  to  be  interpreted  by 
noting  that  the  excised  tissues  become  acid,  so  that  the 
tissues  placed  in  the  pure  salt  solutions  are  really  in  the 
same  state  as  the  tissues  described  in  the  preceding  para- 
graph —  the  tissues  are  really  in  an  acid  solution  plus  cer- 
tain salts  —  only  the  concentration  of  acid  is  lower  in  this 
case  than  in  the  previously  described  experiments. 

{e)  Alkalies  do  not  produce  a  cloudiness  of  kidney 
parenchyma  in  any  concentration.  Sodium,  potassium, 
ammonium,  and  calcium  hydroxides  were  employed  in  con- 
centrations up  to  0.03  normal.  The  superficial  layers  of 
the  tissue  slices  ''dissolve"  in  the  hydroxides,  covering  the 
tissues  with  a  clear  gluey  mass.  After  two  or  three  days 
the  tissues  lose  their  bright  normal  color,  but  the  gra>Tiess 
assumed  is  only  slight.  The  sHces  of  kidney  swell  just  as 
they  do  in  acid  solutions. 

(/)  The  addition  of  any  salt  to  the  solution  of  an  alkali 
does  not  lead  to  any  cloudiness  of  the  tissues,  though  it 
markedly  reduces  the  tendency  of  the  superficial  layers  of 
the  tissues  to  go  into  ''solution,"  and  the  swelHng  of  the 


NEPHRITIS  71 

tissue  fragments  as  a  whole.  I  have  tried  the  chlorides, 
bromides,  iodides,  nitrates,  sulphates,  sulphocyanates,  ace- 
tates, tartrates,  and  citrates  of  sodium,  potassium,  and 
ammonium  in  conjunction  with  the  hydroxides  of  sodium, 
potassium,  and  ammonium  without  effect.  I  have  also 
tried  a  few  strontium  and  barium  salts  with  these 
hydroxides  and  calcium  hydroxide,  employing  all  in 
such  low  concentrations  as  to  prevent  the  formation  of 
precipitates,  but  I  got  no  cloudiness  of  the  immersed 
tissues. 

{g)  The  macroscopic  changes  observed  in  the  kidney 
when  this  is  immersed  in  water,  various  acids,  or  alkalies, 
in  salt  solutions  or  these  in  combination,  show  a  series  of 
interesting  parallels  microscopically. 

A  perfectly  fresh  scraping  from  the  kidney  shows  the  cells 
to  possess  a  fairly  clear  protoplasm  in  which  lie  but  few 
granules.  Even  after  the  kidney  cells  have  been  kept  for 
twenty-four  hours  (simply  in  their  own  moisture,  and  pro- 
tected against  evaporation  by  being  covered)  they  show  no 
change  from  this  appearance.  But  as  soon  as  water 
touches  the  cells,  especially  if  the  organ  has  been  kept  for 
twenty-four  hours,  or  if  they  are  placed  in  any  very  dilute 
acid,  a  grayish  film  is  seen  to  develop  macroscopically,  and 
microscopically  the  cells  are  now  found  thickly  studded  with 
granules.  This  is  the  typical  histological  picture  of  the 
cloudy  swelling  described  in  our  textbooks  of  pathology. 
If  now,  while  such  cells  are  being  observed,  a  little  caustic 
soda  is  allowed  to  run  under  the  cover  slip,  the  cells  as  a 
whole  are  seen  to  swell,  the  granules  to  become  fainter, 
then  fewer,  and  finally  to  disappear  entirely,  and  if  enough 
alkali  is  added  the  whole  goes  into  homogeneous 
''solution." 

The  granules  can  also  be  made  to  disappear  by  the  ad- 
dition of  more  acid ;  they  form,  for  example,  in  very  dilute 


72  NEPHRITIS 

acid,  and  disappear  again  if  the  concentration  of  this  same 
acid  is  raised.  ]\Iost  interesting  is  the  fact  that  this  granu- 
lar appearance  can  be  made  to  come  a  second  time  by  still 
further  increasing  the  concentration  of  the  acid.  Acetic 
acid  will  not  do  this,  but  nitric  acid  will  do  it  promptly. 
If  strong  nitric  acid  is  used  this  second  appearance  of  the 
granules  is  only  a  temporary  affair,  for  they  again  dis- 
appear as  the  whole  tissue  goes  into  ''solution."  With 
the  second  appearance  of  the  granules  the  cells  undergo  a 
marked  shrinkage  from  the  more  swollen  state  attained  pre- 
viously, but  this  shrinkage,  like  the  second  appearance  of 
the  granules,  is  also  only  temporary,  and  the  cell  undergoes 
a  final  enormous  swelling  before  being  ''dissolved." 

§3- 

How  now  are  we  to  interpret  these  various  findings,  and 
what  light  do  they  bring  us  regarding  the  cause  and  the 
essential  nature  of  those  changes  of  like  character,  which 
we  observe  in  the  kidney  in  nephritis  and  which  lead  to  the 
increase  in  its  size  and  to  the  change  in  its  color?  Our  first 
attention  must  be  dedicated  to  the  matter  of  the  increase  in 
the  size  of  the  cells. 

H.  J.  Hamburger  recognized  very  clearly  that  the  funda- 
mental cause  for  the  increase  in  the  size  of  the  cells  affected 
with  cloudy  swelling  lies  in  the  production  of  acid  in  them. 
As  we  have  already  learned,  evidences  of  an  abnormal  pro- 
duction and  accumulation  of  acid  in  the  kidney  occurs  in 
every  case  of  nephritis,  and  so  we  may  make  this  condition, 
which  we  have  already  made  responsible  for  the  albuminuria, 
responsible  for  this  increase  in  the  size  of  the  kidney  also. 
But  how  does  an  abnormal  acid  content  manage  to  bring 
about  the  increased  water  absorption  which  leads  to  the 
increase  in  the  size  of  the  cells  (and  so  of  the  kidney  as  a 
whole)  in  nephritis?     Hamburger  answered  this  question  by 


NEPHRITIS  73 

attributing  an  indirect  effect  to  the  acid,  whereby  this  was 
assumed  to  increase  the  osmotic  concentration  within  the 
cells.  The  enlargement  of  the  cells  in  "cloudy  swelling" 
represents  an  oedema  of  the  affected  cells,  and  this  is  most 
easily  accounted  for  on  the  basis  of  the  colloidal  constitu- 
tion of  living  matter.  1  The  serious  objections  that  can  be 
lodged  against  the  widely-accepted  belief  that  cells  repre- 
sent osmotic  systems  cannot  be  raised  against  the  view 
that  the  (lyophihc  or  emulsion)  colloids  of  the  tissues  and 
their  state  determine  the  quantity  of  water  absorbed  by  a 
cell.  As  is  well  known,  the  amount  of  water  that  such 
colloids  (as  represented  by  gelatine,  fibrin,  and  serum  albu- 
min, for  example)  will  absorb  is  enormously  increased  if  any 
acid  is  present.  This  fact  receives  incidental  illustration 
in  Fig.  I.  On  this  basis,  it  is  easy  to  parallel  the  absorption 
of  water,  and  so  the  enlargement  of  the  cells  and  the  kidney  as 
a  whole,  when  affected  with  nephritis,  with  the  increased 
amount  of  water  absorbed,  say  by  a  gelatine  cube  or  some 
fibrin  particles,  when  instead  of  being  placed  in  water  they  are 
placed  in  a  dilute  acid  of  some  kind.  In  the  case  of  gelatine 
and  fibrin,  and  similarly  in  the  case  of  the  experiments  on 
excised  kidneys,  the  source  of  the  water  for  the  increased 
swelling  is  to  be  found  in  the  solutions  surrounding  these 
colloidal  structures;  in  the  case  of  the  nephritic  kidney, 
in  the  blood  and  lymph  streams  passing  through  the 
organ. 

There  is,  within  certain  limits,  an  increase  in  the  amount 
of  the  swelKng  of  such  emulsion  colloids  as  gelatine  or 
fibrin  with  every  increase  in  the  concentration  of  the  acid 
surrounding  them.  On  this  basis  we  can  understand  the 
increase  in  the  swelling  of  the  kidney  cells  with  every 
increase  in  concentration  of  the  acid  up  to  a  certain  point. 
When  a  certain  optimal  concentration  of  the  acid  is 
1  See  Mariin  H,  Fischer:  (Edema,  85,  New  York,  19 10. 


74 


NEPHRITIS 


exceeded,  the  colloid  swells  less  than  in  weaker  solutions 
(see  Fig.  i).  This  furnishes  a  ready  interpretation  of  the 
finding  detailed  above,  that  on  substituting  nitric  acid  for 
a  weaker  solution  of  acetic  acid,  kidney  and  liver  cells  are 
seen  to  shrink.  Incidentally,  it  is  worth  while  to  empha- 
size that  in  the  great  rapidity  with  which  such  cells  will 
give  up  and  take  up  water,  in  changing  from  a  medium  of 
one  concentration  to  another  having  a  lower  or  a  higher  one, 
lies  a  powerful  argument  against  the  osmotic  pressure  idea 
of  water  absorption  in  cells.  I  have  seen  these  cells  pass 
from  the  swollen  state,  in  a  weak  acetic  acid  solution,  to 
the  greatly  shrunken  state  induced  by  nitric  acid,  and 
through  a  second  swollen  state  into  ''  solution "  in  less 
than  two  seconds.  Equalizations  of  osmotic  differences 
either  through  a  movement  of  solvent,  or  of  dissolved  sub- 
stance, do  not  occur  with  such  velocity. 

We  may  now  turn  to  a  consideration  of  the  changes  in 
tJte  color  of  the  kidney  in  nephritis,  and  see  how^  these  be- 
come interpretable  on  the  basis  of  the  fact  that  in  this 
condition  an  abnormal  amount  of  acid  is  present  in  the 
kidney. 

The  statements  made  above  regarding  the  means  by 
which  a  cloudiness  can  be  produced  in  the  parenchymatous 
cells  of  the  kidney,  or  the  rate  of  development,  or  the  in- 
tensity of  such  a  cloudiness  be  increased  or  decreased,  have 
all  of  them  parallels  in  the  ways  and  means  by  which  protein 
may  be  precipitated  from  one  of  its  '*  solutions,"  or  such  a 
precipitation  be  hastened  or  retarded.  TJie  development  of 
a  cloudiness  in  the  kidney  cells  follows  most  closely  tlie  solution 
and  precipitation  of  such  a  colloid  as  casein.^ 

Casein  ^  is  insoluble  in  water.      It  is  soluble  in  dilute 

^  This  term  is  used  in  Hammarsten^s  sense  and  corresponds  therefore  with 
the  caseinogen  of  Halliburton. 

2  For  a  discussion  of  the  general  properties  of  casein  see  0.  Hammarsten: 
Physiological  Chemistry,  Translated  by  Mandel,  New  York;   E.  Laqueur 


NEPHRITIS  75 

hydroxides,  in  which  state  it  is  electro-negative.  It  is  in 
this  state  that  we  find  the  body  proteins  normally,  as  Wolf- 
gang Pauli  1  has  shown.  When  a  dilute  acid  is  added  to 
such  an  electro-negative  protein,  let  us  say  to  a  solution 
of  casein  in  any  hydroxide,  a  precipitate  of  the  casein 
is  thrown  down.  A  similar  precipitation  of  an  electro- 
negative colloid  occurs  when  our  sections  of  kidney  are 
immersed  in  any  dilute  acid.  The  development  of  a  cloud- 
iness in  tissues  immersed  in  water  is  also  to  be  regarded  as 
a  precipitation  through  a  dilute  acid,  only  in  this  case  the 
tissues  themselves  produce  the  acid.  Similar  conditions 
hold  in  nephritis,  when,  in  consequence  of  the  abnormal  acid 
content  of  the  kidney,  some  of  the  protein  constituents  of 
the  cells  composing  this  organ  are  precipitated.  As  we 
have  already  found  this  same  acid  to  be  responsible  for  an 
increased  affinity  of  the  tissue  colloids  for  water,  it  is  easy 
to  see  how  from  the  two  there  results,  when  water  is  avail- 
able, the  picture  we  designate  ''  cloudy  swelling." 

But  our  analogy  goes  further  than  this.  If  we  continue 
to  add  acid  to  the  reaction  mixture  in  which  our  casein  was 
last  precipitated,  we  find  that  with  an  increase  in  the  con- 
centration of  the  acid  the  casein  goes  back  into  solution. 
This  is  what  we  observe  in  the  kidney  cells  when  we  note 
the  cloudiness  produced  in  a  weak  solution  of  any  acid,  or 
that  found  in  the  nephritic  kidney  on  autopsy,  to  dis- 
appear on  applying  a  stronger  solution  of  the  acid  (say 
acetic  acid)  to  the  kidney.  This  macroscopic  change  has 
its  parallel  in  the  microscopic  disappearance  of  existing 
granules  in  a  cell,  the  seat  of  a  cloudy  swelHng  (found  either 
post  mortem  or  induced  artificially) ,  when  acetic  acid  is  run 
under  the  cover  slip.     But  the  casein  thus  redissolved  in 

and  0.  Sackiir:  Hofmeister's  Beitrage,  3,  193  (1903);  W.  A.  Osborne:  Jour. 
Physiol.  27,  398  (1901);  T.  B.  Robertson:  Jour.  Biol.  Chem.,  2,  317  (1907); 
L.  L.  van  Slyke  and  E.  B.  Hart:  Am.  Chem.  Jour.,  33,  461  (1905). 
^  Wolfgang  Pauli:  Naturwissensch.  Rundschau,  21,  3  (1906). 


76  NEPHRITIS 

such  an  acid  as  acetic  acid  can  be  precipitated  a  second 
time  if  strong  nitric  (or  hydrochloric  or  sulphuric)  acid  is 
allowed  to  flow  into  the  test  tube.  If  the  protein  is  not 
present  in  excessive  amounts,  this  second  precipitate  also 
disappears:  we  say  it  goes  into  solution  in  the  excess  of 
the  nitric  acid.  It  is  not  difficult  to  see  that  this  is  entirely 
analogous  to  the  reappearance  of  granules  in  the  kidney 
cells,  with  subsequent  total  solution  of  the  affected  cells,  on 
the  addition  of  nitric  acid  for  example,  to  cells  in  which  a 
previous  set  of  granules  has  been  made  to  disappear  by  the 
addition  of  acetic  acid. 

Equinormal  solutions  of  different  acids  are  not  equally 
effective  in  producing  a  precipitation  of  casein,  neither 
are  they  equally  effective  in  producing  the  cloudiness  of 
cloudy  swelling.  In  low  concentrations  certain  salts  favor 
the  precipitation  of  casein  in  dilute  acids  while  others 
hinder  this.  The  sulphocyanates  and  iodides  quickly  pre- 
cipitate casein  from  an  acid  solution  in  heavy  curds. 
Equimolecular  solutions  of  the  bromides,  nitrates,  and  chlo- 
rides produce  only  an  opalescence, while  in  citrates  the  casein 
remains  in  solution.  When  arranged  according  to  the  in- 
tensity with  w^hich  these  anions  favor  the  development  of 
a  cloudiness  in  the  kidney  the  order  is  the  same.  Various 
kations,  in  the  dilute  solutions  in  which  they  have  to  be 
used  to  prevent  their  precipitation  as  hydroxides,  do  not 
influence  the  precipitation  of  casein.  Neither  do  they^affect 
the  development  of  cell  cloudiness. 

Kidney  cells  also  follow  the  behavior  of  casein  tow^ard 
alkahes.  All  the  alkahes  make  casein  go  into  solution  and, 
similarly,  the  alkalies  do  not  produce  any  clouding  in 
kidney  cells.  ^     Casein  is  not  precipitated  in  alkaHne  solu- 

^  The  slight  grayness  developed  by  slices  of  kidney,  kept  for  several  days 
in  a  dilute  alkali,  has  its  parallel  in  the  turbidness  which  we  find  developed  in 
alkaline  solutions  of  casein,  when  these  are  kept  for  longer  periods  of  time. 


NEPHRITIS  77 

tion  by  the  addition  of  any  of  the  ordinary  salts.  Neither 
is  a  cloudiness  produced  when  any  salts  are  added  to  slices 
of  liver  or  kidney  immersed  in  a  dilute  alkali. 

Point  for  point  the  analogy  between  the  precipitation  of 
casein  and  the  artificial  development  of  a  cloudiness  in 
kidney  cells  seems  therefore  to  be  complete,  and  since  there 
exists  no  discoverable  difference  between  the  changes  thus 
artificially  induced  in  excised  kidneys  and  those  which 
nature  produces  for  us  in  this  same  organ  in  nephritis,  nor 
yet  in  the  conditions  leading  to  these  changes  in  either  case, 
we  would  seem  to  be  justified  in  considering  all  these 
changes  as  in  essence  the  same,  and  as  caused  funda- 
mentally by  the  same  circumstances. 

As  this  process  of  cloudy  swelling  represents  a  series  of 
changes  in  the  state  of  the  cell  colloids,  it  is  clear  that  the 
employment  of  any  methods  in  its  study  —  such  as  fixing 
agents  and  various  stains  —  which  in  themselves  are  capa- 
ble of  producing  changes  in  the  state  of  cell  colloids,  should 
be  excluded.  Nevertheless,  to  meet  the  possible  objection 
that  what  has  been  described  in  these  pages  as  cloudy 
swelling  might  really  not  be  identical  with  this  change  as 
observed  on  the  autopsy  table,  our  pathologist,  Paul  G. 
Woolley,  generously  offered  to  examine  by  approved  his- 
tological methods  the  tissues  in  which  I  had  produced 
cloudy  swelling  artificially.  He  reports  that  the  pictures 
obtained  are  identical  with  the  most  extreme  grades  of 
cloudy  swelling  that  are  encountered  pathologically. 

In  concluding  these  paragraphs  we  have  to  answer  the 
final  question  of  the  relation  of  the  swelling  of  the  kidney  cells 
to  the  clouding  in  them.  On  the  basis  of  the  fundamental 
work  of  Wolfgang  Pauli  ^  and  his  coworkers,  Hans  Han- 

^  Wo.  Pauli:  Kolloid  Zeitschr.,  7,  241  (1910);  Pauli  and  H.  Handovsky: 
Biochem.  Zeitschr.,  18,  340  (1909)  24,  239  (1910);  H.  Handovsky:  Kolloid 
Zeitschr.,  7,  183,  267  (1910);  Fortschritte  in  der  Kolloidchemie  der 
Eiweisskorper,  Dresden,  191 1;  Karl  Schorr:  Cited  by  Pauli  and  Handovsky. 


78  NEPHRITIS 

dovsky  and  Karl  Schorr,  this  is  easily  done.  As  these  in- 
vestigators have  shown,  the  sweUing  and  solution  of  a 
protein  colloid  (its  hydration)  and  the  loss  of  water  and 
precipitation  of  this  same  colloid  (its  dehydration)  repre- 
sent antagonistic  processes  and  are  therefore  mutually  exclu- 
sive. It  follows  from  this  that  the  swelling  of  the  cells  in 
a  parenchymatous  nephritis,  and  the  development  of  a 
cloudiness  in  them,  can  impossibly  involve  the  same  colloid, 
—  in  other  words,  at  least  two  must  be  involved.  The 
conditions  w^hich  permit  the  one  of  these  to  imbibe  w^ater 
and  so  lead  to  an  increase  in  the  size  of  the  cell  are  of  such 
a  character  as  to  lead  to  the  precipitation  of  another,  and 
so  to  the  cloudiness.  Wolfgang  Paidi  kindly  advised  me  to 
test  out  this  idea  in  a  model  made  by  pouring  a  solution  of 
casein  (prepared  by  saturating  sodium  hydroxide  with 
casein)  into  a  concentrated,  carefully-washed  gelatine 
(20  per  cent)  and  allowing  the  whole  to  stiffen.  When 
plates  are  cut  from  such  a  mixture  they  swell  (absorption 
of  water  by  the  gelatine)  and  become  cloudy  (precipitation 
of  casein)  under  the  same  conditions  (presence  of  acids  and 
various  salts)  as  were  found  above  to  lead  to  a  ''cloudy 
swelling  "  in  slices  of  kidney. 

4.   The  Bleeding  into  and  from  the  Kidney  in  Nephritis 
(Haemorrhage  by  Diapedesis). 

The  blood  that  appears  in  the  urine  in  some  cases  of 
nephritis  may  have  a  purely  traumatic  origin;  in  larger 
part,  however,  pathologists  hold  that  it  gets  from  the 
capillaries  into  the  urine  by  diapedesis.  Through  diapede- 
sis are  also  explained  the  haemorrhages  into  the  kidney 
substance  itself.  As  such  bleeding  does  not  occur  from 
the  normal  kidney,  we  become  interested  in  its  mechanism, 
and  it  becomes  a  part  of  our  problem  to  discover  why  in 


NEPHRITIS  79 

nephritis  such  a  process  of  diapedesis,  which  occurs  also 
in  other  pathological  states,  should  be  especially  prone  to 
appear. 

We  still  lack  a  satisfactory  explanation  of  the  mechanism 
of  diapedesis.  Our  present  teachings  continue  to  partake 
of  the  views  of  von  Recklinghausen  and  Julius  Arnold,  who 
held  that  holes  (so-called  stomata)  exist  in  the  capillaries, 
and  that  through  these  the  red  blood  corpuscles  escape  in 
conditions  associated  with  a  bleeding  by  diapedesis.  But 
such  a  condition,  as  Julius  Cohnheim  pointed  out  years 
ago,  is  grossly  incorrect,  for  what  escapes  from  the  blood 
in  haemorrhage  by  diapedesis  is  not  the  whole  blood,  but 
only  the  red  blood  corpuscles,  and  it  is  inconceivable  how 
holes  which  would  permit  the  passage  of  the  cellular  ele- 
ments of  the  blood  through  them  should  hold  back  the 
liquid  portion  of  the  blood,  Cohnheim  believed  diapedesis 
to  be  dependent  upon  changes  in  the  blood  vessel  walls 
whereby  these  became  abnormally  permeable,  after  which 
he  held  the  blood  pressure  to  be  able  to  force  the  red  blood 
corpuscles  through  them.  How  such  an  abnormal  per- 
meability was  brought  about  he  declared  himself  unable  to 
explain. 

Haemorrhage  by  diapedesis,  while  discussed  by  us  be- 
cause present  in  some  forms  of  nephritis,  is  really,  of  course,  a 
widely  distributed  pathological  phenomenon.  As  is  famil- 
iarly known,  it  occurs  in  any  well-marked  passive  con- 
gestion, produced,  for  example,  by  ligation  of  the  veins  of 
any  of  the  parenchymatous  organs,  of  the  mesenteric  veins, 
or  of  those  coming  from  the  leg  or  the  ear  of  a  rabbit  or 
dog.  But  it  occurs  also  after  ligation  of  the  arterial 
blood  supply  to  a  part,  and  I  have  observed  it  in  the 
entire  absence  of  any  circulation  in  the  legs  of  frogs  so 
ligated  as  to  close  both  arteries  and  veins,  and  kept  in  a 
little  water.     Haemorrhage    by  diapedesis  occurs  also  in 


8o  NEPHRITIS 

conjunction  with  the  acuter  forms  of  inflammation  no 
matter  how  induced. 

It  is  clear  from  these  few  remarks  that  blood  pressure, 
which  might  at  first  sight  be  thought  to  be  of  some  impor- 
tance in  squeezing  the  red  blood  corpuscles  out  of  the  blood 
vessels  into  the  surrounding  tissues,  cannot  be  of  great  im- 
portance in  this  regard,  for  diapedesis  occurs  in  conditions 
associated  Tvith  a  decrease  in  the  blood  pressure,  or,  as 
just  pointed  out,  even  in  its  entire  absence.  What  is 
present  in  all  the  conditions  noted  is  such  a  disturbance 
in  the  circulation  as  to  lead  to  a  state  of  lack  of  ox}'gen  in 
the  tissues,  and,  we  have  to  repeat,  an  abnormal  production 
and  accumulation  of  acids  in  the  affected  regions.  .\nd 
this  is  what  we  have  in  the  kidney  in  nephritis.  But  how 
does  this  now  lead  to  the  diapedesis?  The  answer  is  not 
hard  to  find. 

We  have  already  called  attention  to  the  well-known  fact 
that  the  cells  of  the  living  organism  represent  in  the  main 
a  mixture  of  several  so-called  lyophilic  or  emulsion  colloids. 
Under  normal  circumstances  in  the  body  these  are  in  a 
swollen  state  that  is  similar  to  that  assumed  by  fibrin  or 
gelatine  when  placed  in  water.  If  a  little  acid  is  introduced 
into  such  a  colloid  the  absorption  of  water  by  it  is  enor- 
mously increased,  and  as  we  have  already  pointed  out  be- 
fore, this  is  what  happens  when  acid  is  introduced  into  the 
kidney  (or  into  the  tissues  of  the  other  parenchymatous 
organs,  the  intestine,  the  leg,  or  the  ear),  in  other  words, 
an  "  oedema  "  develops.  But  this  increased  absorption  of 
water  makes  the  tissue  softer  (or  to  put  it  more  technical!}^, 
its  internal  friction  is  decreased  and  its  surface  tension  is 
changed)  and  now  the  red  blood  corpuscle  which  lies  in 
contact  with  its  surface  is  no  longer  held  out  by  the  surface 
layer  of  the  tissue  colloids  (the  blood  vessel  wall)  but  pene- 
trates this  —  is  really  "swallowed"  by  the  tissue.      The 


NEPHRITIS  8i 

increased  fluidity  of  the  kidney  tissues,  after  these  have 
been  treated  with  a  little  acid  in  the  presence  of  water,  is 
readily  observable  under  the  microscope.  The  cells  can 
be  pushed  about  and  molded  on  slight  pressure  in  a  most 
striking  way. 

What  makes  the  red  blood  corpuscle  move  through  the 
tissues  are  inequalities  in  the  stresses  present  in  the  tissue 
colloids.  By  a  process,  the  reverse  of  that  described,  the 
tissue  which  has  once  swallowed  a  red  blood  corpuscle  may 
again  get  rid  of  it,  though  in  practice  such  a  result  is  hardly 
to  be  expected,  for  after  a  softened  tissue  that  has  swallowed 
some  red  blood  corpuscles  has  a  more  normal  circulation 
once  more  restored  to  it,  it  is  likely  to  lose  its  excess  of 
acid,  and  so  its  water,  so  rapidly  that  the  red  blood  cor- 
puscles remain  behind  entangled  in  the  tissues.  As  a  matter 
of  fact  we  know  that  the  red  blood  corpuscles  that  have 
escaped  into  the  tissues  are  usually  absorbed  indirectly, 
after  they  have  disintegrated. 

What  we  have  said  here  regarding  the  red  blood  cor- 
puscles holds  of  course  also  for  the  white  blood  corpuscles 
only  these  possess  in  addition  independent  powers  of  move- 
ment which  are  lacking  to  the  red  blood  corpuscles.^  More 
strictly  in  the  class  with  the  red  blood  corpuscles  belong 
the  bacteria  which  we  know  may  reach  the  kidney  from  any 
part  of  the  body  and  pass  through  the  kidney  substance 
out  into  the  urine. 

Briefly  formulated,  the  problem  of  how  the  red  blood  cor- 
puscles in  nephritis  pass  into  the  tissues  of  the  kidney  or 

^  In  the  discussion  of  the  migration  of  white  blood  corpuscles  in  inflamma- 
tion (chemotaxis)  most  emphasis  is  always  laid  upon  the  changes  that  the 
white  blood  corpuscles  themselves  are  believed  to  suffer  (for  example, 
changes  in  surface  tension),  which  result  in  their  movement  toward  the  in- 
flammatory center.  This  is  only  half  the  problem.  The  changes  in  the 
tissues  themselves  (changes  in  viscosity,  for  example),  produced  through  the 
action  of  the  excitant  of  the  inflammation,  also  play  a  role. 


82  NEPHRITIS 

through  these  out  into  the  urine,  or  the  problem  of  how  white 
blood  corpuscles  or  bacteria  do  this  comes  to  be  the  problem  of 
how  one  colloidal  body  may  pass  through  another,  and  of  the 
laws  that  govern  such  a  passage.  No  holes  are  necessary  in 
order  that  one  colloid  may  pass  through  another,  and  such 
a  passage  is  accomplished  without  one  colloid  losing  its 
identity  in  the  other  or  leaving  behind  it  any  evidence  of  its 
passage. 

The  matter  can  be  prettily  illustrated  by  letting  a  mer- 
cury drop  or  solid  metals  (iron  fragments  or  shot,  or  these 
covered  with  colloidal  material  as  agar-agar  or  collodion), 
under  the  influence  of  gravity,  move  in  all  directions  through 
a  soHdified  gelatine.  The  mercury  is  particularly  suitable, 
for,  while  not  a  colloid,  it  has  the  "  Hquid  "  character  pos- 
sessed by  the  red  and  white  corpuscles.  In  the  body  the  mi- 
gration of  the  blood  corpuscles  (or  metal  fragments,  etc.)  does 
not  of  course  occur  under  the  influence  of  gravity,  but  in 
consequence  of  inequalities  in  the  pressure  exerted  upon  the 
surface  of  these  elements,  occasioned  through  inequalities 
in  the  stresses  present  in  the  tissues  (brought  about  in  turn 
through  local  changes  in  the  water  content  of  the  lyophilic 
colloids  comprising  the  tissues).  And  as  the  question  of 
whether  a  mercury  drop  will  enter  a  solidified  gelatine,  and 
the  rate  at  which  it  will  move  about  in  this  are  matters 
that  have  to  do  with  the  surface  tension  relationships  that 
exist  between  the  mercury  and  the  gelatine,  and  the 
viscosity  of  the  gelatine  (in  its  turn,  affected  by  concentra- 
tion, temperature,  acids,  bases,  and  salts),  so  these  same 
factors  play  a  role  in  diapedesis  as  observed  in  the  hving 
organism. 

In  Fig.  15  is  shown  how  a  mercury  drop  is  unable  to 
penetrate  a  stiffened  gelatine  (3  per  cent)  at  room  tem- 
perature. It  may  be  rolled  about  on  the  surface  of  the 
gelatine  without  entering  it.     If  now  this  experiment  is 


NEPHRITIS 


83 


repeated  at  the  same  temperature,  with  a  stiffened  gela- 
tine of  a  somewhat  lower  concentration,  the  mercury  drop 
enters  it  and  falls  slowly  to  the 
bottom  (Fig.  16,  a,  h,  c).  By 
turning  the  tube  about  (Fig. 
17),  the  mercury  drop  will  move 
in  all  directions  through  the 
stiff  gelatine  in  which  of  course 
no  holes  exist,  and  in  which 
none  remain  after  the  mercury 
has  passed.^ 

The  essential  change  in  the 
gelatine,  which  makes  such  pen- 
etrability possible  in  this  exper- 
iment, was  induced  through 
regulation  of  the  concentration. 
A  similar  change  can  be  induced 
by  raising  the  temperature  some- 
what (not  to  the  point  of  melt- 
ing the  gelatine,  of  course)  or,  in 
the  presence  of  water,  by  adding 
a  little  acid.  This  approximates 
most  closely  the  change  that 
occurs  in  the  body  when  in  pas- 
sive congestion,  for  example,  a 
diapedesis  into  the  cedematous 
tissues  is  noted.  What  happens  under  such  circumstances 
can  also  be  mimicked  with  some  gelatine  cubes  and  a  few 
mercury  drops.  If  two  gelatine  cubes  are  placed,  the  one 
in  water,   the   other   in   a   dilute  acid,   the  one   in  acid 

^  It  is  this  property  of  colloids  which  explains  easily  why  small  wounds 
made  in  the  hving  animal  close  immediately.  The  property  of  colloids, 
which  gives  them  such  great  interest  biologically,  is  the  fact  that  they  com- 
bine in  one  the  properties  of  liquids  (surface  tension,  viscosity,  diffusion  of 
dissolved  particles)  with  the  properties  of  solids  (maintenance  of  form). 


Fig.   15. 


84 


NEPHRITIS 


undergoes  a  swelling,  which  after  a  time  reaches  a  stage  at 
which  it  will  readily  admit  of  the  passage  of  a  mercury 
drop,  while  the  control  in  water  will  not  do  so. 


b 

Fig.  1 6. 


5.    On  the  Origin  and  the  Different  Types  of  Tube  Casts. 

In  this  section  we  will  discuss  how  the  abnormal  acid 
content  of  the  kidney  in  nephritis  leads  to  the  formation  of 
casts.  At  the  same  time  we  will  learn  how  the  various 
types  of  casts  that  are  discovered  in  the  urine  in  nephritis 


NEPHRITIS 


85 


bear  a  simple  relationship  to  each  other ;  how,  in  fact,  it  is 
possible  to  convert  one  type  of  cast  into  another,  and  back 
again  if  we  so  choose,  under  the  con- 
ditions found  in  the  kidney  and  in  the 
urine  in  nephritis. 

What  must  be  the  effect  of  the  ab- 
normal production  or  accumulation  of 
acid  in  the  kidney,  so  far  as  this  prob- 
lem of  casts  is  concerned,  may  be  de- 
termined in  any  one  or  all  of  several 
ways.  We  may  simply  leave  the  nor- 
mal kidney,  freshly  removed  from  the 
body,  to  itself,  protect  it  against  evapo- 
ration, and  study  the  effects  of  the  post 
mortem  development  of  acid  in  it.  Or, 
we  may  slice  the  kidney  into  several 
pieces  and  place  them  in  water,  or, 
finally,  we  may  place  such  slices  directly 
into  slightly  acidified  water.  The  kid- 
neys of  guinea  pigs  and  rabbits  furnish 
excellent  material  and  it  is  on  these 
that  the  following  observations  were 
made. 

When  we  take  a  fresh  kidney  that 
has  been  cut  across  and  squeeze  it  gently,  we  only  see 
a  little  blood  ooze  from  the  blood  vessels.  If  we  scrape 
the  surface  and  put  a  little  of  the  scrapings  on  a  sUde, 
we  find  little  more  than  some  red  blood  corpuscles  mixed 
in  with  a  little  granular  material.  We  find  that  it  is 
difficult  to  obtain  any  kidney  parenchyma  cells,  —  they 
do  not  separate  easily  from  their  attachments.  The 
same  kidney,  preserved  for  several  days,  presents  a 
somewhat  different  appearance.  The  surface  may  not 
be  quite  so  glistening  when   cut,   and   on  squeezing  the 


Fig.  17. 


86  NEPHRITIS 

organ  turbid  points  arise  over  the  surface  of  the  kidney 
which,  when  examined  microscopically,  are  seen  to  be  made 
up  of  epithelial  cells  which  have  loosened  from  the  kidney 
tubules.  These  may  be  single,  or  joined  together  in  groups, 
and  with  them  are  again  found  the  red  blood  cells  and  the 
granular  detritus  that  was  observed  in  a  scraping  from  the 
perfectly  fresh  kidney. 

A  somewhat  different  picture  is  presented  by  the  sections 
of  kidney  that  are  placed  in  water.  These  tissues  become 
gray  more  quickly  than  the  tissues  that  do  not  come  in  con- 
tact with  water,  and  develop  an  opaque  appearance.  The 
normal  kidney  markings  become  gradually  more  and  more 
obscured,  and  the  tissues  as  a  w^hole  are  seen  to  swell  some- 
what. The  whole  makes  up  the  typical  picture  of  that 
which  the  pathologists  call  cloudy  swelHng,  and  the  nature 
of  which  we  discussed  in  a  foregoing  section.  A  scraping 
from  the  surface  of  such  a  gray  kidney  shows  a  large  num- 
ber of  free  epithelial  cells,  w^hich  one  has  no  difficulty  in 
recognizing  as  coming  from  glomerular  tufts  and  from  the 
uriniferous  tubules.  In  making  the  scraping  one  notices, 
moreover,  that  while  vigorous  scraping  yielded  little  or 
nothing  when  appHed  to  the  healthy  kidney,  it  is  no  trick 
at  all  to  get  an  abundant  amount  of  material  from  the 
surface  of  a  kidney  that  has  lain  in  water  for  a  day  or  two. 
One  notices,  moreover,  that  the  numerous  epithelial  cells 
are  swollen  and  studded  with  granules.  But  beside  the 
individual  epithelial  cells  one  notices  groups  of  these,  and 
then  casts  with  rounded  ends  of  whole  tubes.  One  has  no 
difficulty  in  recognizing  these  as  duplicates  of  the  epithelial 
casts  found  in  the  urine  in  certain  t}^es  of  nephritis. 

But  the  most  striking  picture  is  that  presented  by  the 
sections  of  kidney  that  we  have  thrown  into  a  very  weak 
acid  of  some  kind.  In  this  the  cloudy  swelHng  of  the  sHces 
of  kidneys  already  described  occurs  very  rapidly.     A  gentle 


NEPHRITIS 


87 


b 

Fig.  18. 


88  NEPHRITIS 

scraping  jrom  the  surface  of  a  kidney  slice,  treated  with  such  a 
dilute  acid  (0.002  normal  lactic,  for  example),  shows  in 
several  hours  after  immersion  a  granular  detritus,  separate 
epithelial  cells,  groups  of  epithelial  cells,  and  casts  of  various 
kinds  (Fig.  18,  a  and  h).  When  the  kidney  is  simply  gently 
squeezed  and  its  surface  touched  to  a  slide,  and  this  is  then  ex- 
amined 7?ticroscopically,  one  cannot  escape  the  impression 
that  he  is  examining  a  centrifuged  urinary  specimen  from  a 
case  of  acute  nephritis.  The  epithelial  cells,  the  epithelial 
casts,  the  granular  casts  are  all  there.  One  misses  only 
tJte  hyaline  cast,  hut  this  can  he  promptly  ohtained  by  simply 
adding  a  little  stronger  acid  to  our  specimen  under  the  micro- 
scope, when  our  granular  casts  are  seen  to  lose  their  gran- 
ules, swell  somewhat  more  decidedly,  and  become  difficultly 
visible.  Scattered  nuclei  may  stick  to  the  casts,  but  if 
enough  acid  is  added,  these  too  go,  so  that  only  the  greatly 
swollen,  entirely  hyaline  ''  cylindroids "  of  some  authors 
remain.  Or,  we  can  assure  ourselves  of  a  generous  yield  of 
hyaline  casts  and  cyhndroids  from  the  start  if  we  simply 
increase  the  acid  concentration  into  which  we  drop  our 
kidney  slices,  or  prolong  their  residence  in  the  solution. 

We  can  convert  the  granular  casts  into  hyaline  ones 
quite  as  easily  through  the  addition  of  an  alkali  as  through 
the  addition  of  an  acid,  and  if  the  kidney  slices  are  from 
the  first  dropped  into  a  dilute  alkali,  only  hyaline  casts  are 
obtained.  The  hyahne  casts  produced  through  the  acids 
can  be  converted  back  into  granular  casts,  if  we  wish,  by 
simply  running  a  little  salt  under  the  cover  slip.  A  sul- 
phocyanate  is  particularly  good  for  this  purpose,  but  if  we 
wish  to  use  a  salt  that  is  more  "  physiological "  in  nature, 
sodium  nitrate  or  sodium  chloride  will  do.  The  hyaline 
casts  produced  through  alkalies  can  also  be  converted 
into  granular  ones,  though  to  accomplish  this  they  must 
be    treated    with    an    equinormal    acid.     Why    all    these 


I 


NEPHRITIS 


89 


transformations  are  possible  is,  of  course,  readily  intel- 
ligible when  the  experiments  on  cloudy  swelling  as  detailed 
in  the  previous  sections  are  recalled  to  mind. 

In  Fig.  19  is  shown  the  appearance  of  a  gentle  scraping 
taken  from  a  sHce  of  kidney  that  had  lain  in  water  for 
several  hours.  A  granular  cell  detritus  and  isolated  casts 
characterize    such    a    specimen.     Nuclear    fragments    are 


Fig.  19. 

prominent,  and  the  epithehal  cells  may  in  places  still  be 
made  out.  The  cells  are  granular.  In  Fig.  20,  a,  is  shown 
a  scraping  similarly  prepared  from  a  sHce  of  kidney  that 
had  lain  in  a  0.005  normal  acetic  acid  for  three  hours.  The 
cast  formation  (falHng  apart  of  the  kidney)  is  a  far  more 
prominent  feature.  In  the  cast  occupying  the  central  point 
in  the  photomicrograph  remnants  of  an  epithehal  structure 
are  still  present.  In  the  casts  lying  above  this  all  evidences 
of  nuclear  structure  have   disappeared.     They  are  filled 


90 


NEPHRITIS 


with  fine  granules.  When  these  casts  were  treated  with  a 
stronger  solution  of  acetic  acid  they  became  hyaline,  as 
shown  in  Fig.  20,  b. 

It  is  clear  therefore  that  under  the  influence  of  a  little 
acid  the  kidney  drops  apart  into  its  morphological  elements. 
While  these  are  firmly  cemented  together  in  the  healthy 
kidney  (as  witness  the  attempt  to  obtain  them  by  scraping 


Fig.  2q. 

the  surface  of  the  kidney  with  a  knife),  they  are  separated 
with  the  greatest  ease  after  the  kidney  has  lain  in  acid  for 
a  while.  The  answer  as  to  why  the  kidney  falls  apart  as 
it  does  under  the  influence  of  acid  it  is  needless  to  discuss, 
but  the  \'iew  that  some  of  the  (colloidal)  ''  cement  sub- 
stance "  is  easily  "  soluble  "  or  is  easily  ''  digested  "  in  weak 
acids  at  once  suggests  itself.  Such  a  view  finds  support  in 
our  previous  considerations  of  albuminuria  and  the  fact, 
easily  observed  in  these  experiments,  that  the  solutions  in 


NEPHRITIS 


91 


which  the  kidney  slices  lie  come  to  contain  with  time  pro- 
gressively larger  amounts  of  albumin.  That  some  con- 
stituents of  the  kidney  (or  of  any  other  organ)  are  more 
readily  soluble  in  an  acid  than  are  others,  is  clearly  enough 
evident  under  the  microscope.  The  nuclei  of  the  cells  still 
retain  their  outlines,  for  example,  in  concentrations  of  acid 
in  which  the  protoplasm  generally  has  become  entirely 
hyaline.  The  action  of  the  acid  could  be  aided  and  abetted, 
of  course,  by  various  enzymes. 

What  is  important  to  us,  from  the  standpoint  of  the  theory 
of  nephritis,  is  the  way  in  which  the  kidney  falls  apart.  The 
epithelial  cells  tend  to  stick  together  while  they  separate  in  mass 
from  their  supporting  membrane.  This  marks  the  origin  of 
the  urinary  cast  which,  in  clinical  cases,  is  washed  down  into 
the  bladder  by  the  force  of  the  secreted  urine. 

These  simple  facts  regarding  the  origin  of  casts,  and  the 
conditions  under  which  the  one  type  may  be  converted 
into  another,  are  not  without  some  cHnical  significance.  In 
treatises  on  medicine  and  in  works  on  cHnical  diagnosis 
much  has  been  said,  not  only  regarding  the  significance  of 
the  appearance  of  casts  in  the  urine,  but  of  the  significance 
of  the  different  kinds  of  casts.  It  seems  to  me  that  the 
experiments  that  have  just  been  detailed  urge  upon  one 
the  necessity  of  caution  in  drawing  too  sweeping  conclu- 
sions from  such  data.  So  far  as  mere  numbers  of  casts  are 
concerned  it  requires  no  special  emphasis  to  reah'ze  that 
great  numbers  of  casts  present  in  the  urine  at  one  time, 
while  indicative  of  a  more  extensive  involvement  of  the 
kidney  parenchyma,  may  not  be  as  significant  as  a  lesser 
number  present  over  longer  periods  of  time.  The  aggre- 
gate destruction  may  in  the  latter  case,  of  course,  be  much 
greater  than  in  the  former  (a  condition  further  modified 
in  the  living  organism  by  the  rate  and  quantity  of  the  re- 
generation occurring  in  the  kidney). 


92 


NEPHRITIS 


In  judging  of  the  meaning  of  the  character  of  the  cast, 
whether  epithehal,  granular,  or  hyahne,  one  must  be  ex- 
ceedingly careful.  We  have  seen,  first  of  all,  that  the 
epithelial  cast  is  readily  convertible  into  either  the  gran- 
ular or  the  hyaline,  depending  only  upon  how  much  acid 
is  present  and  the  length  of  time  that  it  is  allowed  to  act ; 
and  the  hyaline,  we  have  seen,  can  be  reconverted  into  the 
granular.  The  thought  might  suggest  itself  that  we  use 
the  nature  of  the  cast  as  an  index  of  the  degree  of  the  acid 
concentration  in  the  kidney  and  so  as  a  measure  of  the  in- 
tensity of  the  nephritis.  But  this  may  not  be  done,  for 
we  know  from  autopsy  findings  that  a  nephritis  need  not 
affect  all  the  parts  of  a  kidney  equally,  or  at  the  same  time, 
and  the  urine  represents  a  mixed  product  of  the  whole 
kidney.  Moreover,  the  urine  itself  varies  so  in  composition 
under  different  (physiological)  circumstances  that  it  may 
alter  the  character  of  the  cast  in  its  passage  through  the 
ureter  and  bladder,  no  matter  what  its  nature  when  it  left 
the  kidney.  A  highly  acid  urine  would  on  the  whole  tend 
to  yield  granular  or,  if  sufficiently  high,  hyaline  casts.  An 
alkaline  urine  would  tend  to  yield  only  hyaline  casts.  On 
the  other  hand,  the  salts  of  the  urine  would  tend  to 
counteract  the  acid  and  make  the  casts  not  only  smaller 
(loss  of  water  by  the  colloid)  but  more  granular  (precipitation 
of  the  colloid).  One  can  easily  satisfy  himself  of  these 
facts  by  providing  himself  with  casts  from  a  clinical  case  of 
acute  nephritis,  or  from  such  kidneys  as  I  have  described, 
and  examining  them  under  the  microscope,  while  a  little  acid, 
or  this  in  conjunction  with  various  salts,  is  allowed  to  run 
under  the  cover  slips  of  the  preparations. 

In  concluding  this  section  it  is  well  to  revert  for  a  moment 
to  the  question  of  albuminuria.  It  is  possible  to  test  the 
idea  that  albuminuria  results  from  a  "  solution  "  of  the 
proteins  of  the  kidney  under  the  influence  of  an  acid  in 


NEPHRITIS 


93 


conjunction  with  these  experiments  on  the  formation  of 
casts.  If  we  take  a  perfectly  fresh  kidney  from  either  a  rabbit 
or  a  guinea  pig,  cut  it  into  several  slices,  and  then  wash  the 
pieces  a  few  times  in  water  or  a  ''  physiological  "0.9  per 
cent  NaCl  solution,  so  as  to  get  rid  of  the  blood  in  the 
kidney,  we  find  thereafter  that  the  wash  water  gives  little 
or  no  reaction  for  albumin.  But  if  we  permit  the  pieces  of 
kidney  to  lie  in  the  wash  water  until  next  day,  we  have  no 
difficulty  in  getting  the  albumin  reaction.  Still  more 
rapidly  do  we  get  this  reaction  if  we  immerse  the  washed 
slices  of  kidney  from  the  start  in  a  weak  acid  solution. 
Then  we  get  the  reaction  for  albumin  promptly.  If  we 
pipette  off  the  sediment  found  about  the  kidney  pieces  and 
examine  this  under  the  microscope,  we  find  at  the  same  time 
various  kinds  of  casts.  But  the  albumin  is  not  simply 
due  to  these,  for  we  get  a  marked  albumin  reaction  after 
carefully  filtering  the  solution  about  the  kidney  pieces. 

III.     THE   DISTURBANCES   IN   SECRETION 
IN   NEPHRITIS. 

I.  General  Considerations. 

The  changes  observed  in  the  secretion  of  urine  in  any 
case  of  nephritis  fall  into  two  groups:  the  changes  in  the 
amount  secreted  in  any  unit  of  time,  and  the  changes  in 
the  quantitative  composition  of  the  urine.  In  all  except 
the  so-called  chronic  interstitial  types  of  nephritis  the  secre- 
tion of  water  is  diminished.  In  the  chronic  interstitial 
types  it  is  said  to  be  increased.  So  far  as  the  secretion  of 
dissolved  substances  in  nephritis  is  concerned,  it  is  gener- 
ally accepted  that  (diet  duly  considered !)  there  exists  not 
only  a  diminution  in  the  total  amount  of  dissolved  sub- 
stances ehminated,  but  variations  in  the  proportion  of  the 
dissolved  substances  ehminated  when  compared  with  each 


94  NEPHRITIS 

other  and  regarded  in  the  hght  of  the  way  in  which  these 
same  substances  are  eliminated  during  health.  What 
happens  here  is  very  interesting.  We  find  that  certain  sub- 
stances may  be  eUminated  as  well  by  the  diseased  kidney 
as  by  the  normal.  Certain  other  substances  are  ehminated 
in  much  smaller  amounts  than  is  normal,  so  small,  in  fact, 
that  it  is  often  said  not  at  all.  Experiments  and  observa- 
tions to  indicate  that  a  nephritic  kidney  may  secrete  yet 
other  substances  even  better  than  a  normal  kidney  are  not 
on  record  so  far  as  I  know.  Quantity  of  urine  duly  con- 
sidered, such  a  thing  is  theoretically  not  impossible. 

Before  we  can  to  advantage  consider  the  secretion  of 
water  and  of  dissolved  substances  by  the  kidney,  we  shall 
first  have  to  return  to  a  further  consideration  of  the  posi- 
tion occupied  by  chronic  interstitial  nephritis  in  our  gen- 
eral classification  of  the  nephritides.  As  is  generally  known, 
the  secretion  of  water  by  the  patient  with  chronic  intersti- 
tial nephritis  is  not  diminished  as  in  all  the  parenchyma- 
tous forms,  it  is  normal  in  amount,  or,  as  the  majority  of 
cHnicians  and  pathologists  are  wont  to  say,  it  is  increased 
in  amount.  In  discussing  this  problem  of  why  in  chronic 
interstitial  nephritis  wx  do  not  have  the  diminution  in  out- 
put of  water  observed  in  the  parench^miatous  forms,  we 
shall  at  the  same  time  touch  upon  the  questions  of  the  in- 
creased blood  pressure  and  the  heart  hypertrophy  observed 
in  the  chronic  interstitial  forms  and  absent  from  the  paren- 
ch}/Tnatous  forms. 

2.   Further  Remarks  on  the  Relation  of  Chronic  Intersti- 
tial Nephritis  to  the  Parenchymatous  Types. 

I.  To  the  claim  that  in  chronic  interstitial  nephritis  the 
amount  of  urine  secreted  is  increased,  serious  objection 
must  be  made.  It  is  better  to  simply  say  that  the  out- 
put is  normal.     Urinary  secretion  is  normal  if  (with  due 


NEPHRITIS  95 

regard  to  loss  of  water  through  skin,  lungs,  and  intestinal 
tract)  all  the  water  consumed  by  an  individual  is  excreted 
again,  as  urine,  —  that  is  to  say,  none  is  retained  (oedema) 
and  not  more  than  has  been  consumed  is  excreted  (abnormal 
loss).  If  a  man  consumes  only  a  Hter  of  water  a  day  and 
secretes  a  liter  of  urine  (skin,  etc.,  being  ignored)  his  uri- 
nary secretion  is  normal,  and  if  he  consumes  twenty  liters 
and  secretes  twenty  it  is  normal.  We  may  differ  as  to 
which  of  these  amounts,  if  either,  we  consider  as  normal 
(better  optimal)  from  the  standpoint  of  consumption,  but 
so  far  as  secretion  is  concerned,  both  are  normal.  And  for 
this  reason  I  would  insist  that  the  patient  with  chronic  in- 
terstitial nephritis,  who  happens  to  consume  in  response  to 
his  tastes  three  Hters  of  water  and  so  secretes  three  liters 
of  urine  (skin,  etc.,  again  ignored)  has  not  an  increased 
urinary  output,  but  a  normal  one.  So  far  as  water  output 
is  concerned  the  patient  with  chronic  interstitial  nephritis  is 
simply  not  nephritic. 

But  he  is  not  a  nephritic  from  other  standpoints  either. 
He  has  not  the  oedema  of  the  parenchymatous  types.  He 
has  not  the  evidence  of  excessive  acidity  in  his  urine, 
as  already  pointed  out  in  discussing  R.  Hober^s  analy- 
ses of  the  urine  in  nephritis.  Neither  has  he  the  albumin, 
the  casts,  or  the  blood  that  are  found  in  parenchymatous 
nephritis.  We  can  carry  this  still  further.  If  a  patient 
without  these  signs  and  symptoms  dies,  and  on  the  autopsy 
table  we  find  the  small  kidneys  {"  small  red  kidneys  ")  that 
we  diagnose  anatomically  as  chronic  interstitial  nephritis, 
then  the  parenchyma  cells  of  the  kidney  —  the  only  parts 
of  the  kidney  that  are  concerned  with  its  physiological 
function  —  are  also  found  looking  normal.  The  small,  red 
kidneys  are,  except  for  size,  normal  kidneys.  So  far, 
chronic  interstitial  nephritis  is  not  nephritis  at  all,  it  is  an 
atrophy  of  the  kidney.    This  is  the  typical  picture  of  the 


96  NEPHRITIS 

man  who  lives  for  months  or  years  without  symptoms  of 
kidney  disease,  and  in  whom  we  diagnose  chronic  inter- 
stitial nephritis  post  mortem. 

Let  us  now  consider  the  man  who  has  been  less  fortu- 
nate in  this  regard,  the  patient  in  whom  we  have  before 
death  diagnosed  a  chronic  interstitial  nephritis  because  we 
have  found  a  few  casts,  occasional  traces  of  albumin,  and 
let  us  add,  an  arteriosclerosis,  a  hypertrophy  of  the  left 
ventricle,  and  a  high  blood  pressure.  To  drag  in  a  symptom 
often  referred  to  in  these  cases  let  us  suppose  that  he 
tells  us  that  he  has  to  rise  one  or  more  times  nightly  to 
urinate.  The  more  pronounced  the  albuminuria,  and  the 
more  steady  the  appearance  of  casts,  the  more  certain  are 
we  of  finding,  on  autopsy,  not  the  small,  red  kidney,  but  the 
swelled  (small)  gray  kidney!  In  other  words  we  get  the 
(physiological)  characteristics  of  parenchymatous  nephri- 
tis added  to  what  (morphologically)  we  call  chronic  inter- 
stitial nephritis.  And  when  we  study  these  cases  carefully 
we  find  that,  as  the  albuminuria  and  the  formation  of  casts 
increase,  the  (''increased")  urinary  output  also  falls,  and 
along  with  it  we  are  Hkely  to  note  the  first  evidences  of  an 
oedema.  Symptomless  and  signless,  interstitial  nephritis  is 
therefore  essentially  an  atrophy  of  the  kidney,  and  the  in- 
dividual so  affected  behaves  and  dies  like  the  animal  that 
has  had  its  kidney  substance  removed  by  successive  opera- 
tions down  to  the  physiological  minimum.  Chronic  inter- 
stitial nephritis  with  casts,  albumin,  etc.,  is  the  mixed 
picture  resulting  from  a  (morphologically)  chronic  intersti- 
tial nephritis  plus  a  parenchymatous  nephritis. 

All  that  now  remains  unexplained  in  this  picture  of 
chronic  interstitial  nephritis  is  the  arteriosclerosis,  the 
hypertrophy  of  the  heart,  the  increased  blood  pressure,  and 
the  incident  that  the  urinary  secretion  is  of  such  a  charac- 
ter that  the  patient  is  disturbed  at  night.     Let  us  take 


NEPHRITIS  97 

these  up  seriatim,  and  in  our  discussion  let  us  not  be  misled 
into  that  pitfall  which  would  make  of  a  sick  animal  a  some- 
thing for  which  the  established  laws  of  physiology  are  no 
longer  valid. 

2.  The  bearing  of  arteriosclerosis  upon  kidney  disease 
has  to  be  considered  from  two  viewpoints.  Is  the  arterio- 
sclerosis responsible  for  the  kidney  disease,  or  vice  versa? 
The  kidney  associated  with  arteriosclerosis  is  the  con- 
tracted kidney,  the  chronic  interstitial  type.  Such  a 
kidney  shows  as  a  rule  the  greatest  variety  of  morpho- 
logical changes.  While  certain  regions  are  entirely  normal 
in  appearance,  other  patches  show  characteristic  ''  degener- 
ative "  changes,  as  evidenced  by  the  presence  of  cells  that 
are  swollen  and  granular,  or  perhaps  have  lost  their  nuclei 
and  are  disintegrated  {localized  parenchymatous  nephritis). 
To  take  the  place  of  the  dead  cells  we  may  find  new  paren- 
chyma cells  forming,  or  there  may  be  found  evidences  of 
connective  tissue  proliferation  indicating  the  ultimate  for- 
mation of  a  scar.^ 

This  patchy  appearance,  resulting  from  a  mixture  of  nor- 
mal, degenerating  and  regenerating  cellular  elements  in  the 
kidney,  stands  in  marked  contrast  to  the  uniformity  of  ap- 
pearance presented  by  a  kidney  that  has  been  poisoned, 
say,  with  the  toxines  of  an  acute  infectious  disease.  Here, 
in  a  certain  sense,  all  parts  of  the  kidney  are  affected  and 
to  about  the  same  degree.  The  appearances  correspond 
with  the  fact  that  in  the  first  case  small  patches  of  the 
kidneys  are  successively  affected  by  local  disturbances  in 
the  circulation  in  the  kidney,  in  the  second  all  the  cells  are 

^  The  morphological  changes  that  characterize  chronic  interstitial  nephri- 
tis are  in  no  sense  specific.  They  represent  the  consequences  of  a  progres- 
sive destruction  of  piece  after  piece  of  kidney  parenchyma  and  replacement 
of  this  by  scar  tissue.  Entirely  similar  pictures  are  obtainable  in  any  gland  in 
which  the  blood  supply  is  cut  down  directly,  or  indirectly  through  ligation 
of  the  secretory  duct,  as  Dudley  Tail  has  shown. 


98  NEPHRITIS 

at  once  subjected  to  the  same  destructive  agent.  All  this 
suggests  that  arteriosclerosis  is  under  such  circumstances 
the  primary  cause  of  the  nephritis,  and  not  a  result  of  the 
same.  Whether  nephritis  may  in  its  turn  lead  to  a  reten- 
tion of  toxic  substances,  these  to  an  arteriosclerosis,  and  so 
to  the  establishment  of  a  vicious  circle  is  another  question. 
While  satisfactory  experiments  and  cHnical  observations 
proving  that  nephritis  is  followed  by  an  arteriosclerosis 
can  hardly  be  said  to  exist,  an  enormous  number  show 
clearly  enough  that  nephritis  does  follow  arteriosclerosis. 
From  all  of  which  it  is  clear  that  the  treatment  of  chronic 
interstitial  nephritis  (secondary  to  arteriosclerosis)  calls 
not  so  much  for  a  treatment  of  nephritis  as  for  a  treatment 
of  arteriosclerosis,  —  and  the  more  liberal  rules  laid  down 
for  the  guidance  of  the  patient  with  chronic  interstitial  ne- 
phritis than  for  him  who  suffers  from  any  of  the  paren- 
ch3niiatous  forms  constitutes  the  tacit  acceptance  of  this 
belief  on  the  part  of  the  therapist.^ 

3.  Just  as  the  arteriosclerosis  associated  with  kidney 
disease  is  not  to  be  discussed  as  the  consequence,  but 
rather  as  the  cause  of  the  kidney  disease,  so  the  hypertrophy 
of  the  heart  observed  in  such  cases  is  more  the  consequence 
of  the  arterial  disease  than  of  the  kidney  disease.  This  is 
clearly  enough  evidenced  by  the  fact  that  the  (physiologi- 
cally) worst  types  of  nephritis  are  those  least  liable  to  be 

^  In  spite  of  years  of  experimental  work,  the  numerous  observ^ers  who 
have  tried  to  reproduce  experimentally  the  picture  of  chronic  interstitial 
nephritis  in  animals  can  scarcely  be  said  to  have  been  successful.  Their 
failure  resides  in  their  methods,  and  it  may  safely  be  predicted  that  their 
present  methods  never  can  be  successful.  As  must  appear  from  the  re- 
marks made  here,  the  picture  of  chronic  interstitial  nephritis  will  be  pro- 
duced only  if  a  method  is  devised  (analogous  to  the  arteriosclerosis  observed 
in  the  vessels  of  the  kidney  parenchyma)  which  will  little  by  little  destroy 
one  fragment  of  kidney  after  the  other.  Injections  of  lead,  arsenic,  chro- 
mium, etc.,  do  not  attack  the  kidney  in  any  such  locahzed  ways  —  they 
attack,  generally  speaking,  all  portions  of  the  kidney  equally  and  at  once. 


J 


NEPHRITIS  99 

associated  with  any  hypertrophy  of  the  heart.  That,  on 
the  other  hand,  enormous  hypertrophies  of  the  heart  may 
be  associated  with  no  kidney  symptoms  whatsoever  is 
famihar  to  everyone. 

In  discussing  this  subject  of  heart  hypertrophy  and 
chronic  interstitial  nephritis  we  seem,  as  cHnicians,  all  too 
often  to  lose  sight  of  the  fact  that  the  hypertrophy  of  the 
heart  results  in  this  case,  as  in  any  case,  from  the  increased 
demands  for  work  made  upon  the  heart.  In  the  hyper- 
trophy associated  with  arteriosclerosis  these  increased  de- 
mands result  from  at  least  two  changes  in  the  circulation: 
the  reduction  in  the  calibre  of  the  blood  vessels,  and  the 
loss  of  the  elasticity  of  the  blood-vessel  walls. 

It  should  be  clearly  borne  in  mind  that  the  mere  roughen- 
ing of  the  blood-vessel  walls  has  nothing  to  do  with  in- 
creasing the  work  of  the  heart.  The  friction  encountered  in 
driving  the  blood  through  the  vessels  is  not  that  of  blood 
against  blood  vessel  wall.  Since  the  blood  ''  wets  "  the 
blood  vessel  walls  the  friction  is  that  of  one  layer  of  liquid 
over  another. 

With  a  given  kind  of  blood,  the  blood  vessels  determine 
how  much  energy  is  required  to  force  the  blood  through 
them,  only  so  far  as  their  length  (constant  in  body),  diame- 
ter, and  elasticity  are  concerned.  So  far  as  the  effect  of 
changes  in  diameter  is  concerned  (and  in  arteriosclerosis 
the  diameter  of  the  blood  vessels  is  diminished) ,  it  must  be 
borne  in  mind  that  the  force  required  to  drive  a  given  vol- 
ume of  liquid  through  a  tube  increases  about  as  the  cube 
when  the  cross  section  is  diminished  one-half.  The  loss  of 
elasticity  becomes  a  factor  because,  under  physiological 
conditions,  in  the  time  of  a  single  contraction  of  the  ven- 
tricle an  amount  of  blood,  the  equivalent  of  that  ejected 
from  the  heart,  is  not  at  once  pushed  along  the  entire 
arterial  and  capillary  bed  out  into  the  veins.    Under  normal 


loo  NEPHRITIS 

circumstances  it  is  simply  thrown  into  the  elastic  arterial 
system  which  dilates  somewhat,  and  then,  during  the  period 
that  follows  the  systole  of  the  heart,  the  elastic  forces  resi- 
dent in  the  arteries  slowly  recoil  and  squeeze  the  blood  on 
out  into  the  veins.  When  this  elasticity  is  markedly 
diminished,  the  heart  must  in  that  proportion  force  its 
quota  of  blood  during  the  time  of  each  systole  at  once 
through  the  whole  arterial  and  capillary  system,  and  this 
demands  an  enormously  greater  outlay  of  energy. 

A  third  factor  for  the  hypertrophy  of  the  heart  might  re- 
side in  the  blood  itself.  A  Hquid  moves  through  a  tube 
with  greater  and  greater  difficulty  the  more  viscid  it  is. 
Anything  that  would  increase  the  viscosity  of  the  blood 
would  therefore  increase  the  amount  of  work  demanded  of 
the  heart  to  push  the  blood  ahead.  The  viscosity  of  such 
colloidal  solutions  as  the  blood  is  enormously  increased  by 
sHght  traces  of  acid  (P.  vo7i  Schroeder,^  W.  B,  Hardy, '^  and 
especially  Wolfgang  Pauli  and  Hans  Handovsky  ^)  and  so 
this  factor  which  comes  into  play  not  only  in  nephritis  but 
in  hard  work  of  any  kind  (laborers,  athletes)  needs  to  be 
considered.  While  certain  clinical  studies  of  the  viscosity 
of  the  blood  have  not  as  yet  brought  any  proof  to  show 
that  this  undergoes  any  material  change  in  nephritis,  that 
such  changes  might  well  be  expected  is  indicated  by  certain 
experiments  of  R.  Burton-Opitz,^  who  found  venous  blood 
to  have  a  higher  viscosity  than  arterial,  due  to  the  CO2  in 
it,  and  the  blood  of  dogs  after  the  feeding  of  proteins  (acid 
production)  to  have  a  higher  viscosity  than  before  such 
feeding. 

4.  From  what  has  been  said  it  is  clear  that  we  cannot 

1  P.  von  Schroeder:  Zeitschr.  f.  physik.  Chem.,  45,  106  (1903). 

2  W.  B.  Hardy:  Journal  of  Physiology,  33,  251  (1905);  Proceedings  of  the 
Royal  Society,  79,  413  (1907). 

2  Wo.  Pauli  and  H.  Handovsky:  Biochem.  Zeitschr.,  18,  340  (1909). 
^R,  Burton-Opiiz:  Pfliiger's  Archiv,  119,  359  (1907). 


NEPHRITIS  loi 

regard  the  heart  hypertrophy  as  something  primary,  but  as 
something  secondary  —  as  an  example  of  the  wide  range 
of  adaptation  to  changed  conditions  of  which  the  cells  and 
organs  of  our  body  are  capable.  The  high  blood  pressure, 
far  from  being  in  itself  an  evil  thing,  is  decidedly  good  — 
only  through  the  increased  pressure  are  the  various  tissues  of 
the  body  guaranteed  a  blood  supply  sufficient  to  satisfy  their 
physiological  demands.  This  holds  for  the  kidney  as  for 
any  other  organ  in  the  body.  Only  the  increased  blood 
pressure  renders  it  possible  that  the  normal  parts  remain- 
ing in  an  arteriosclerotic  kidney  maintain  what  I  have 
called  the  normal  secretion  of  water  from  such  a  kidney. 
While  conditions  may  exist  or  arise  in  the  body  which 
make  the  high  blood  pressure  in  itself  dangerous  (weaken- 
ing of  blood  vessel  walls  and  rupture),  a  high  blood  pressure 
must  with  this  exception  not  be  regarded  as  something  evil, 
but  as  an  attempt  on  the  part  of  the  body  to  keep  our  various 
organs  working  at  their  physiological  optimum.  Measures 
that  merely  reduce  blood  pressure  can  therefore  hardly  be 
looked  upon  with  favor.  We  must  treat  the  underlying  cause 
of  the  increased  blood  pressure,  not  the  blood  pressure  itself. 
To  apply  this  to  the  kidney,  with  which  we  happen  to  be 
dealing  here,  I  can  recall  several  cases  of  chronic  interstitial 
nephritis  with  high  blood  pressure  and  cardiac  hypertrophy 
in  which  a  too  enthusiastic  desire  to  reduce  the  blood 
pressure  led  to  the  use  of  the  nitrites,  and  with  serious  con- 
sequences. While  the  blood  pressure  fell,  the  urinary  out- 
put also  decreased,  the  albumin  rose,  and  casts  became 
numerous.  In  other  words,  the  general  fall  in  blood  pres- 
sure made  for  a  decreased  circulation  of  blood  through 
the  kidney,  and  so  for  an  aggravation  of  the  kidney  state. 
Only  when  we  think  that  such  a  bad  result  will  not  follow 
the  use  of  nitrites  are  we  justified  in  using  them.  One 
case  developed   immediately  after  a  single  dose  of  amyl 


I02  NEPHRITIS 

nitrite  a  complete  anuria  which  some  eight  days  later  killed 
the  patient. 

5.  It  remains  for  us  to  discuss  the  question  of  why  the 
patient  \\ith  chronic  interstitial  nephritis  must  rise  to  uri- 
nate at  night.  Such  is  the  case  even  when  there  exist  no 
pathological  conditions  in  the  lower  parts  of  the  urinary 
tract  that  might  be  considered  responsible.  But  on  the 
basis  of  our  analysis,  which  makes  chronic  interstitial  ne- 
phritis more  an  atrophy  of  the  kidney  than  a  nephritis 
(except  in  the  small  patches  which  are  Httle  by  little  cut 
out  from  the  kidney),  the  matter  is  easily  understood. 

As  the  studies  of  Bradford  have  shown,  we  can  spare  some 
two-thirds  or  even  more  of  our  total  kidney  substance 
without  serious  inconvenience.  It  is  in  about  such  a  state 
that  the  man  with  chronic  interstitial  nephritis  finds  him- 
self. What  must  be  the  conditions  for  urinary  secretion  in 
such  an  individual?  The  normal  man  with  all  his  kidney 
substance  intact  will  secrete  the  five  hundred,  or  say  a 
thousand,  cubic  centimeters  of  water  consumed  with  a  meal 
in  the  two  or  three  hours  that  follow  this  meal.  The 
patient  with  only  a  third  the  normal  kidney  substance 
must  take,  other  things  being  equal,  three  times  as  long  to 
secrete  this  same  amount  of  water,  in  other  words,  six  to 
nine  hours.  While  the  normal  man  will  be  largely  rid  of 
the  water  he  has  drunk  with  his  supper  when  he  urinates 
for  the  last  time  before  going  to  bed,  the  man  with  the 
chronic  interstitial  nephritis  will  continue  to  secrete  urine 
into  his  bladder  for  hours  afterward,  and  as  this  organ 
fills  he  must  rise  during  the  night  to  empty  it. 

3.   The  Secretion  of  Water  by  the  Nephritic  Kidney. 

In  support  of  the  thesis  that  an  abnormal  accumulation 
or  production  of  acid  in  the  kidney  constitutes  the  basic 
cause  of  every  nephritis,  it  would  be  sufficient  in  this 


NEPHRITIS  103 

section  merely  to  show  that  such  a  condition  always  leads 
to  a  decrease  in  the  secretion  of  water  by  the  kidney. 
We  shall,  however,  not  stop  with  this  but  try  to  indicate  in 
a  little  more  detail  where  lies  the  point  of  attack  for  the 
acid  that  is  responsible  for  such  a  change  in  secretion. 

It  is  an  easy  matter  to  show  that  the  direct  introduction  of 
acid  into  the  kidney,  or  any  method  capable  of  leading  to  an 
abnormal  acid  content  in  the  kidney,  is  followed  by  a  decrease 
in  urinary  secretion  which  may  go  to  the  point  of  absolute 
stoppage.  This  is  clearly  evident  in  the  accompanying 
drawings  which  have  been  constructed  from  the  experi- 
ments detailed  in  various  parts  of  this  paper. 

Figure  22  on  page  142  has  been  introduced  to  show  the 
normal  secretion  of  urine  in  three  rabbits,  kept  on  a  mixed 
diet,  when  these  are  brought  into  the  laboratory  and  are 
loosely  tied  into  an  animal  holder.  When  the  animals  are 
snugly  tied  into  a  holder,  the  urinary  secretion  is  decreased 
in  amount.  This  is  clear  from  Fig.  23,  in  which  are  shown 
the  curves  for  the  urinary  secretions  obtained  in  the  animals 
that  were  rendered  albuminuric  by  this  means  (Experiments 
22,  23,  24,  and  25).  If  instead  of  such  a  general  state  of 
lack  of  oxygen  in  the  body  we  interfere  locally  with  the 
blood  supply  to  the  kidney,  as  through  clamping  of  the 
renal  blood  vessels,  the  same  great  fall  in  urinary  output 
is  observed,  as  is  evidenced  in  the  lowermost  curve  of  Fig.  28. 
But  to  show  that  it  is  really  the  acid  developed  in  the 
body  as  a  whole,  or  in  the  kidney  specifically,  that  under 
these  circumstances  is  responsible  for  such  a  fall  in  secre- 
tion, it  is  best  to  inject  the  acid  directly.  The  effect  of  such 
a  proceeding  is  shown  in  Fig.  24  based  on  Experiments  12, 
13,  and  14.  It  would  be  purposeless  to  multiply  these  ex- 
periments to  further  support  the  contention  that  an  abnor- 
mal acid  content  in  the  kidney  leads  to  a  decrease  in  the 
secretion  of  water.    As  a  matter  of  fact,  this  finds  daily 


I04  NEPHRITIS 

corroboration  in  the  decreased  urinary  output  observed  in 
all  those  clinical  cases,  such  as  heart  disease,  respiratory 
disease,  etc.,  which  we  know  to  be  associated  with  an  ab- 
normal accumulation  and  production  of  acids  in  the  body. 

But  how  may  we  imagine  the  acid  to  be  effective  in  this 
regard?  A  proper  answer  to  this  question  demands  a  criti- 
cal review  of  all  the  various  theories  that  have  been  pro- 
posed from  time  to  time  to  explain  the  mechanism  of 
normal  urinary  secretion,  and  this  would  lead  us  too  far 
afield.^  We  can,  however,  help  toward  a  more  circum- 
scribed formulation  of  the  whole  problem. 

Defined  physicochemically,  the  problem  of  water  secre- 
tion by  the  kidney  is  essentially  the  problem  of  how  water 
contained  in  the  blood  is  made  to  pass  through  a  solid 
(hydrophylic)  colloidal  membrane,  this  being  represented,  in 
the  case  of  the  kidney,  by  the  various  cells  and  their  inter- 
cellular substances  that  lie  between  the  blood  on  the  one 
hand  and  the  urine  on  the  other.  Two  possible  sources 
for  the  forces  necessary  to  get  the  water  through  this  mem- 
brane are  available.  The  membrane  may  be  perfectly 
passive  and  the  blood  itself  suffer  changes  which  result  in 
driving  the  water  through  the  membrane ;  or  the  membrane 
itself  may  be  concerned  in  the  process,  in  that  it  first  ab- 
sorbs water  from  the  blood  to  give  it  up  again  later  into 
the  uriniferous  tubules;  or,  finally,  both  may 'act  together. 

Two  theories  of  urinary  secretion  that  have  considered 
changes  in  the  blood  as  primarily  responsible  for  the  giving 

1  See  R.  Heidenhain:  Hermann's  Handbuch  d.  Physiologic,  5,  Leipzig, 
1883;  jE.  Waymouth  Reid:  Schaefer's  Textbook  of  Physiology,  1,  261,  Lon- 
don and  Edinburgh,  1898;  E.  H.  Starling:  ibid  1,  285;  Oppenheimer's  Hand- 
buch d.  Biochemie,  3,  206,  Jena,  1909;  H.  J.  Hamburger:  Osmotischer 
Druck  und  lonenlehre,  2,  93,  Wiesbaden,  1904;  E.  Overton:  Nagel's 
Handbuch  der  Physiologic,  2,  774,  Braunschweig,  1907;  0.  Cohnhcim: 
ibid,  2,  607;  R.  Hober:  Kordnyi-Richter,  Physikalische  Chemie  und  Medi- 
zin,  1,  295,  Leipzig,  1907;  Martin  H.  Fischer:  (Edema,  186,  New  York, 
1910;  KoUoidchemische  Beihefte,  2,  304  (191 1). 


NEPHRITIS 


105 


off  of  water  by  the  kidney  have  attained  special  distinc- 
tion. The  older  of  these  is  that  of  Bowman  and  Ludwig 
which,  briefly  put,  holds  changes  in  blood  pressure  respon- 
sible for  the  changes  in  the  amount  of  urine  secreted. 
An  increase  in  blood  pressure  is  held  to  yield  a  freer  secre- 
tion of  urine,  a  decrease  the  reverse.  In  spite  of  Heiden- 
hain's  clear-cut  criticism  of  this  theory  it  still  finds  wide 
acceptance  and,  since  it  is  the  chief  one  that  is  discussed  by 
pathologists  and  cUnicians,  a  few  words  regarding  it  may 
not  be  amiss. 

Pathologists  and  cHnicians  are  inclined  to  adopt  the 
mechanical  pressure  theory  of  urinary  secretion  and  to 
apply  it  to  the  problem  of  nephritis,  because  it  has  been 
generally  observed  that  in  the  acute  types  of  (parenchyma- 
tous) nephritis,  which  are  associated  with  a  decrease  in  uri- 
nary secretion,  no  appreciable  changes  in  blood  pressure  are 
to  be  noted,  while  in  the  chronic  interstitial  types,  which 
are  generally  held  to  show  an  increase  in  urinary  secretion, 
there  is  often  a  marked  increase  in  general  blood  pressure. 
And  yet  that  the  blood  pressure  per  se  can  have  nothing  to 
do  with  this  matter  of  water  secretion  is  clearly  evidenced 
by  the  experiments  of  Ponfick  ^  and  Magnus  2  who  found 
that  when  the  blood  pressure  is  artificially  increased  in  the 
normal  animal,  through  injection  of  blood  or  blood  plasma, 
no  increase  in  urinary  output  results. 

In  the  light  of  what  we  know  to-day  regarding  the  filtra- 
tion under  pressure  of  any  Kquid  through  a  colloidal  mem- 
brane —  and  that  is  the  problem  involved  when  we  hold 
that  under  the  influence  of  blood  pressure  water  is  squeezed 
through  the  colloidal  urinary  membrane  to  make  the  urine 
—  this  filtration  hypothesis  must  be  abandoned  entirely. 

On  the  pressure  basis,   the  urinary  secretion  problem 

^Ponfick:  Virchow's  Archiv,  62,  277  (1875). 

2  Magnus:  Arch.  f.  exp.  Path.  u.  Pharm.,  45,  210  (1901). 


io6  NEPHRITIS 

would  be  analogous  to  the  filtration  of  water,  for  example, 
through  a  thin  gelatine  membrane,  and  the  amount  of 
pressure  required  to  do  this  is  out  of  all  proportion  to  that 
available  in  the  li\'ing  animal.  The  maximal  filtration 
pressure  available  in  the  body  is  the  maximal  blood  pres- 
sure, and  one  equal  to  250  millimeters  of  mercury  easily 
covers  even  pathological  states  of  high  blood  pressure. 
Yet  we  need  no  such  pressures  to  get  a  urinary  secretion. 
A  normal  blood  pressure  suffices  to  enable  our  kidneys  to 
get  rid  of  all  the  water  we  may  be  pleased  to  consume  and 
Gottlieb  and  Magnus  ^  have  shown  that  under  certain  cir- 
cumstances a  secretion  of  urine  can  still  be  obtained  when 
a  blood  pressure  of  only  9  to  12  millimeters  of  mercury  is 
available.  But  even  if  one  were  disincKned  to  regard 
such  a  state  as  '' physiological,"  and  so  insisted  on  125 
millimeters  of  pressure,  or  to  cover  the  pathological  states, 
250  milHmeters,  we  could  still  get  no  filtration  of  water 
through  a  colloidal  membrane  of  the  t}'pe  that  character- 
izes the  kidney.  As  the  studies  of  H.  Bechhold  -  have 
shoTVTi,  five  to  ten  atmospheres,  in  other  words,  five  to 
ten  times  760  milHmeters  of  mercury  are  necessary  before 
water  can  be  squeezed  through  a  thin  layer  of  gelatine. 
By  treating  the  gelatine  with  various  chemicals  it  is  possible 
to  increase  its  permeabiHty  to  water.  But  the  chemicals 
most  effective  in  this  regard  still  leave  the  gelatine  mem- 
brane in  a  state  where  it  demands  half  an  atmosphere 
pressure,  in  other  words,  380  milHmeters  of  mercury.  The 
chemical  substances  that  thus  alter  the  permeabiHty  of  the 
gelatine  filtration  membranes  are  all  such  as  either  precipi- 
tate or  change  (denature)  the  character  of  the  gelatine. 
We  might  therefore  recaU  the  precipitations  (cloudy  sweH- 
ing)  observed  in  kidney  ceUs  in  cHnical  cases  of  nephritis, 

^  Gottluh  and  Magmis:  Archiv.  f.  exp.  Path.  u.  Pharm.,  45,  223  (1901). 
2  H.  Bechliold:  Kolloid  Zeitschr.  3,  3,  33  (1907). 


NEPHRITIS 


107 


or  in  those  of  our  kidney  sections  put  into  this  state  by 
artificial  means,  and  so  think  to  help  ourselves  over  some 
difficulties,  by  saying  that  under  these  circumstances  the 
urinary  membrane  becomes  more  ''  permeable."  Actually, 
we  only  get  ourselves  more  involved,  for  the  very  con- 
ditions (acute  parenchymatous  nephritis) ,  which  in  the  liv- 
ing animal  show  these  membrane  changes,  are  those  in 
which  urinary  secretion  is  most  definitely  diminished} 

Very  evidently,  therefore,  if  we  note  changes  in  urinary 
secretion  with  changes  in  blood  pressure,  the  secretory 
changes  are  not  to  be  attributed  to  the  changes  in  blood 
pressure  per  se,  but  to  some  of  the  accompaniments  of  such 
changes  in  blood  pressure.  Heidenhain  expressed  this 
thought  by  saying  that  it  was  not  the  pressure  which  de- 
termined the  secretion,  but  the  amount  of  blood  passing 
through  the  kidney.  But  this  also  does  not  adequately  ex- 
press the  problem.  It  is  not  alone  the  amount  of  blood 
but  the  kind  of  blood.  Only  when  blood  rich  in  oxygen 
and  low  in  carbon  dioxide  goes  through  the  kidney  do  we 
have  secretion.  No  amount  of  venous  blood  going  through 
the  organ  will  yield  a  drop  of  urine.  Since  the  blood  does 
not  carry  its  great  oxygen  content  for  its  own  benefit,  and 
since  the  arterial  blood  which  enters  the  kidney  leaves  this 
organ  as  venous  blood,  it  is  clear  that  the  cells  here  use  it 
up,  and  since  the  kidney  actively  secreting  water  uses  up 
more  oxygen  and  yields  more  carbon  dioxide  ^  than  a  rest- 

^  The  recent  experiments  of  Alfred  Schoep,  Kolloid  Zeitschr.,  8,  80  (191 1), 
can  also  not  be  called  upon  for  help.  That  Schoep  got  a  filtration  of  water 
through  collodion  membranes  with  only  a  few  millimeters  of  mercury  pressure 
constitutes  an  experimental  fact  that  cannot  immediately  be  used  for 
biological  purposes.  Collodion  is  a  lyophilic  colloid  in  such  solvents  as 
ether,  alcohol,  etc.  It  is  a  lyophobic  one  in  water  and  therefore  does  not 
represent  a  membrane  at  all  of  the  nature  of  those  existing  in  the  living 
animal  (which  are  lyophilic  in  water). 

2  See  Barcroft  and  T.  G.  Brodie:  Journal  of  Physiology,  32,  18  (1904);  33, 
52  (1905)- 


io8  NEPHRITIS 

ing  kidney,  it  follows  that  this  secretion  demands  work  on  the 
part  of  the  kidney  structures — the  secreting  colloidal  7nemhrane. 
Further  evidence  that  the  kidney  does  such  work  is  furnished 
by  the  higher  temperature  that  prevails  in  the  urine  over 
that  prevailing  in  the  blood  from  which  it  is  derived. 

A  second  theory  of  urinary  secretion  that  regards  changes 
in  the  composition  of  the  blood  as  of  primary  importance 
in  determining  the  secretion  of  water  from  the  kidney  is 
that  proposed  by  Isador  Trauhe}  According  to  this 
author,  changes  in  the  surface  tension  of  the  blood  are  re- 
sponsible for  a  squeezing  of  fluid  through  the  capillary 
structures  composing  the  kidney  (the  cells  and  intercellular 
substances)  that  he  between  the  blood  on  the  one  hand  and 
the  urine  on  the  other.  The  ingenious  ideas  of  Trauhe 
have  scarcely  received  the  attention  from  physiologists  and 
pathologists  that  they  deserve.  In  connection  with  our 
problem  I  should  only  Hke  to  point  out  that  should  they 
ultimately  prove  adequate  to  account  for  the  phenomena 
of  secretion  —  a  subject  of  doubt  to  my  mind,  chiefly  be- 
cause during  secretion  the  secretory  membrane  does  work 
and  in  proportion  to  the  amount  of  secretion,  while  Trauhe' s 
ideas  do  not  demand  this  —  the  introduction  of  acid  into 
the  blood  or  into  the  kidney  would  be  associated  with  such 
changes  in  the  surface  tension  of  the  blood  and  in  the 
capillarity  of  the  kidney  as  to  render  the  changes  in  secre- 
tion observed  in  nephritis  readily  intelligible. 

The  theories  of  urinary  secretion  which  lay  the  main 
stress  upon  the  kidney  cells  themselves,  as  the  sources  for 
the  energy  required  to  separate  water  from  the  blood,  may 
be  briefly  considered  under  three  heads  —  the  "physiologi- 
cal" or  "secretory"  theory,  the  osmotic  theory,  and  the 
colloidal  theory. 

^Isador  Trauhe:  Pfluger's  Archiv,  105,  541  (1904);  123,  419  (1908);  133, 
511  (1910);  Biochem.  Zeitschr.,  10,  371  (1908);  16,  182  (1909). 


NEPHRITIS 


109 


The  "physiological"  or  "secretory"  theory  of  urinary 
secretion  suffers  from  the  defects  of  every  such  "physio- 
logical" theory  —  it  explains  nothing.  The  osmotic  theory 
suffers  through  its  inadequacy.  In  spite  of  all  one's  re- 
luctance to  give  it  up,  when  one  considers  its  tempting 
simplicity  and  the  wealth  of  biological  fact  that  its  dis- 
cussion and  experimental  study  have  yielded,  it  seems  now 
as  though  it  would  scarcely  be  able  to  maintain  even  a  par- 
tial role  in  the  phenomena  of  water  absorption  and  secre- 
tion as  observed  in  plant  or  animal  cells.  ^  If  the  osmotic 
theory  of  absorption  and  secretion  has  to  be  reHnquished 
in  working  with  individual  cells,  it  will  have  to  go  all  the 
more  certainly  in  the  special  problem  of  absorption  and 
secretion  as  presented  to  us  in  the  kidney. 

1  have  suggested  that  the  explanation  of  urinary  secre- 
tion be  sought  in  the  colloidal  constitution  of  the  kidney 
and  in  the  physicochemical  changes  that  this  suffers  under 
the  various  conditions  which  we  know  to  influence  the 
secretion  of  water  from  this  organ.-  The  separation  of 
water  from  the  blood  by  the  urinary  membrane)  that  is,  all 
the  structures  that  He  between  the  blood  on  the  one  hand 
and  the  urine  on  the  other)  involves  two  processes  —  an 
absorption  of  water  from  the  blood,  and  a  subsequent  giv- 
ing off  of  this  same  water  out  into  the  uriniferous  tubules. 
How  is  this  accomplished? 

As  already  pointed  out,  the  urinary  membrane  is  built 
up  of  a  series  of  (hydrophilic)  emulsion  colloids.  That  half 
of  the  process  of  urinary  secretion  which  consists  of  an  ab- 
sorption of  water  from  the  blood  by  the  urinary  membrane 
is  entirely  analogous  to  the  absorption  of  water  by  fibrin, 
gelatine,  or  serum  albumin,  —  technically  put,  it  consists  of 

^See  Wolfgang  Pauli:  Sitzungsberich.  d.  Wiener  Akad.  Math-naturw. 
Klasse,  113,  38  (1904);  Martin  H.  Fischer:  Physiology  of  .Alimentation, 
182-187,  267-269.     New  York,  1907;  CEdema,  85.     New  York,  1910. 

2  Martin  H.  Fischer:  (Edema,  180.     New  York,  19 10. 


no  AEPHRITIS 

a  hydration  of  some  or  all  of  the  (hydrophilic)  emulsion  col- 
loids composing  the  kidney.  The  other  half  of  the  process 
of  urinary  secretion  consists  in  a  giving  up  of  this  absorbed 
water;  it  is  analogous  to  the  loss  of  water  by  fibrin,  gela- 
tine, or  serum  albumin,  in  other  words,  to  the  dehydration  of 
a  (hydrophiKc)  emulsion  colloid.  To  accompKsh  the  secre- 
tion of  urine  a  cycle  of  changes  must  therefore  occur  in  the 
kidney,  which  leads  first  to  the  absorption  of  water  and  then 
to  its  secretion.  Let  us  ask  of  what  such  a  cycle  of  changes 
might  consist,  and  though  in  the  case  of  the  kidney  we  ven- 
ture here  upon  treacherous  ground,  a  few  experimentally 
well-estabhshed  facts  point  out  a  road  rather  clearly. 

In  discussing  the  problem  of  absorption^  which  appar- 
ently is  to  be  regarded  in  every  sense  as  the  mirror  image 
of  secretion,  I  pointed  out  how  the  carbonic  acid  produc- 
tion in  cells  may  be  one  —  or  under  physiological  conditions 
the  chief  —  factor  in  determining  the  absorption  of  water 
from  the  peritoneal  cavity  or  the  intestinal  tract.  Experi- 
mental observations  seem  to  indicate  that  the  following 
happens:  the  cells  of  the  peritoneum  or  of  the  intestinal 
tract  produce  carbonic  acid.  This  increases  the  hydration 
capacity  of  the  colloids  constituting  the  peritoneum  or  in- 
testinal tract  for  water,  and  so  if  any  is  present  in  either 
location  it  is  absorbed.  But  the  arterial  blood  entering 
the  peritoneum  or  the  mucous  membrane  of  the  intestine 
has  a  lower  carbon  dioxide  tension  than  that  found  in  the 
cells  here,  and  so  this  diffuses  over  into  the  blood.  As  this 
enters  the  blood  the  capacity  of  the  blood  colloids  for  hold- 
ing water  is  increased  (as  is  evidenced  microscopically  by 
a  swelHng  of  the  blood  corpuscles  in  a  venous  blood,  and 
physicochemically  by  an  increase  in  the  viscosity  of  the 
blood).  Between  the  increased  capacity  of  the  blood  to 
carry  water,  and  the  now  diminished  capacity  of  the  cells 

^Martin  H.  Fischer:  KoUoidchemische  Beihefte,  2,  304  (191 1). 


NEPHRITIS  III 

of  the  peritoneum  and  intestinal  tract  to  hold  on  to  it,  the 
water  previously  absorbed  from  the  peritoneal  cavity  or 
the  intestinal  lumen  is  now  dragged  over  into  the  blood. 
As  long  as  the  circulation  is  maintained  water  must  there- 
fore be  absorbed  from  the  peritoneum  or  the  lumen  of  the 
intestine,  and  as  steadily  be  lost  on  the  opposite  side  of  the 
absorbing  membrane  into  the  blood. 

In  the  case  of  the  kidney,  a  reverse  series  of  changes 
brings  about  a  secretion  of  water.  To  render  secretion 
possible  we  must  first  of  all  supply  the  kidney  with  oxygen. 
In  the  process  of  water  secretion  by  the  kidney  this  oxygen 
is  not  only  used  up  but  carbon  dioxide  is  produced,  and 
the  loss  of  one  and  the  production  of  the  other  run  the 
higher  the  greater  the  amount  of  water  secreted  by  the 
kidney.^  In  the  carbon  dioxide  production  in  the  cells  of 
the  urinary  membrane  we  have,  therefore,  the  estabhshment 
of  conditions  which  increase  the  capacity  of  the  colloids 
here  for  absorbing  water.  In  the  loss  of  this  same  carbon 
dioxide  to  the  blood  we  have  subsequently  the  cause  for  the 
loss  of  the  previously  absorbed  water  out  into  the  space  of 
Bowman's  capsule  or  the  uriniferous  tubules.  The  only 
part  of  water  secretion  by  the  kidney  that  this  simple  in- 
terpretation does  not  explain  is  why  the  water  is  lost 
toward  the  lumen,  and  not  back  into  the  blood  with  the 
carbon  dioxide.  But  for  this  a  simple  explanation  (based 
on  certain  anatomical  relationships  existing  in  the  kidney 
and  on  differences  in  rates  of  diffusion)  can  also  be  given, 
as  I  hope  to  show  at  another  time  in  discussing  some  col- 
loidal models  of  secretion. 

As  I  have  previously  pointed  out,^  the  kidney  is  not 
alone  involved  in  this  matter  of  urinary  secretion,  but  the 

1  Barcroft  and  T.  G.  Brodie:  Journal  of  Physiology,  32,  i8  (1904);  33,  52 

(1905)- 

2  Martin  H.  Fischer:  (Edema,  184.     New  York,  1910. 


112  NEPHRITIS 

blood  as  well,  and,  somewhat  more  remotely,  all  the  tissues 
of  the  body.  We  have  already  touched  upon  the  fact  that 
only  arterial  blood  will  yield  a  secretion,  and  that  no 
amount  of  venous  blood  will  do  so.  But  aside  from  this 
important  fact  it  must  always  be  borne  in  mind  that  the 
mere  coursing  of  blood  through  the  kidney  does  not  repre- 
sent the  existence  of  an  inexhaustible  fountain  of  water  out 
of  which  urine  can  be  manufactured  as  is  so  frequently  done 
by  physiological  and  clinical  workers.  The  water  found  in 
the  blood  is  ordinarily  to  be  regarded  as  bound  to  the 
colloids  of  the  blood.  Only  as  these  suffer  a  change  which 
makes  them  incapable  of  holding  as  much  water  as  they 
once  did,  or  the  colloids  of  the  urinary  membrane  develop 
an  avidity  for  water  that  overtops  that  of  the  blood  col- 
loids for  this  same  water,  does  water  from  the  blood  be- 
come available  for  absorption  (preparatory  for  secretion) 
by  the  kidney.  The  body  tissues  generally  play  a  role  in 
the  whole  problem  as  they  give  up  or  take  water  away  from 
the  blood.  Other  things  being  equal,  it  is  evident  that  the 
kidney  ^\dll  secrete  water  the  more  easily,  the  less  firmly  it 
is  bound  to  the  colloids  of  the  blood. 

These  remarks  have  all  been  necessary  in  order  to  show 
w^hy  it  is  that  the  abnormal  production  or  accumulation  of 
acid  in  the  kidney,  as  occurs  in  nephritis,  must  be  followed 
by  a  decrease  in  the  secretion  of  water  (urine)  from  the 
kidney.  The  acid  must  interfere,  first  of  all,  with  the 
chemical  (enz}Tnatic)  changes  in  the  kidney  cells  them- 
selves, which  are  responsible  for  the  normal  oxidation  proc- 
esses that  occur  here  (such  as  the  production  of  caibon 
dioxide).  While  such  an  increase  in  the  amount  of  acid 
held  in  the  kidney  as  occurs  in  nephritis,  does  not  inter- 
fere with  the  absorption  of  water  from  the  blood,  favors  it, 
rather  (as  evidenced  by  the  swelling  of  the  kidney),  it  in- 
terferes decidedly  with  the  subsequent  loss  of  the  absorbed 


NEPHRITIS  113 

water  which  constitutes  the  palpable  external  evidence  of 
secretion.  The  loss  of  the  acid  to  the  blood  must  be  ren- 
dered the  more  difficult  the  higher  the  amount  of  acid 
already  present  here,  —  wherefore  the  question  of  the 
amount  of  acid  contained  in  the  body  as  a  whole  becomes 
an  important  factor  in  the  problem  of  nephritis.  As  a  final 
word  let  us  point  out  the  fact  that  the  nephritic  kidney  in 
swelling  (as  it  possesses  a  firm  capsule)  compresses  its  vascu- 
lar supply.  In  consequence  of  this  it  not  only  decreases, 
through  the  decrease  in  the  absolute  amount  of  blood 
going  through  the  kidney,  its  opportunities  for  losing  such 
acid  as  it  has  already  accumulated,  but  places  its  com- 
ponent cells  in  a  position  where  an  abnormal  acid  produc- 
tion is  immensely  favored  (lack  of  oxygen) .  All  these  facts 
must  be  borne  in  mind,  and  point  the  way  to  be  followed 
when  we  come  to  discuss  the  matter  of  treatment. 

4.  The  Changes  in  the  Secretion  of  Dissolved  Substances 
by  the  Nephritic  Kidney. 

As  already  noted,  the  nephritic  kidney  shows  devia- 
tions from  the  normal  secretion  of  dissolved  substances 
by  it  in  two  directions.  There  is,  first  of  all,  a  decrease 
(other  conditions  remaining  the  same)  in  the  absolute 
amounts  of  the  various  substances  secreted,  and  second,  in 
the  relative  proportion  that  these  bear  to  each  other  when 
compared  with  the  secretion  of  these  same  substances  as 
observed  in  health.  The  nephritic  kidney  secretes  some 
substances  as  well  as  does  the  healthy  kidney,  others  de- 
cidedly less  well.  It  is  our  problem  to  say  how  such  a  con- 
dition as  an  acid  production  in  the  kidney  brings  such  a 
state  of  affairs  to  pass.  In  order  to  do  this  we  must  recall 
some  of  the  facts  of  normal  secretion  by  the  kidney. 

As  is  famiUar  to  everyone,  a  secretion  of  some  sub- 
stances proportionately  more  easily  than  others,  in  other 


114  NEPHRITIS 

words,  a  ''selective"  secretion  by  the  kidney,  such  as  we 
have  just  outlined,  is  not  characteristic  of  the  diseased 
kidney,  but  of  the  healthy  kidney  as  well.  This  is  really 
the  rock  on  which  most  of  the  mechanical,  or  to  use  a 
broader  and  better  term,  nonvitaHstic  or  physicochemical 
conceptions  of  urinary  secretion  have  foundered,  —  and 
these  founderings  have  given  momentary  comfort  to  those 
who  believe  that  kidney  secretion,  as  many  another  physio- 
logical phenomenon,  is  "vital"  in  character.  But  such 
a  pessimism  would  seem  to  be  premature,  for  we  are 
already  famiHar  in  physical  chemistry  with  not  a  few  sys- 
tems in  which  differences  in  the  concentration  of  any  sub- 
stance are  easily  maintained  over  indefinitely  long  periods 
of  time,  and,  of  course,  without  the  assistance  of  those 
"pecuHar"  forces  believed  by  some  to  inhabit  the  Hving 
cell.  Reference  is  here  made  to  the  differences  in  the  dis- 
tribution {distribution  coefficient)  of  any  substance  between  two 
phases. 

Through  the  work  of  Hans  Meyer  and  E.  Overton  the 
differences  in  the  solubility  of  such  substances  as  alcohol, 
ether,  chloroform,  morphine,  cocaine,  etc.,  in  water  and  in 
fats  and  fathke  bodies  (lipoids)  —  their  distribution  co- 
efficients between  two  solvents  —  have  been  shown  to  ex- 
plain very  satisfactorily  why  these  substances  not  only 
diffuse  with  greater  speed  into  and  through  cells,  especially 
rich  in  the  fatlike  bodies  (the  fat  cells  and  the  cells  of  the 
central  nervous  system),  than  into  and  through  such  as  con- 
tain these  in  smaller  amounts  (yellow  elastic  tissue,  white 
fibrous  tissue) ,  but  why  in  the  end  they  are  found  in  larger 
absolute  amounts  in  some  tissues  than  in  others. 

A  second  property  of  protoplasm  which  permits  one  cell 
or  tissue  to  take  up  more  of  any  given  substance,  and  this 
more  speedily  than  is  the  case  with  another  cell,  is  the 
character  of  the  colloids  contained  in  the  cells  and  the 


NEPHRITIS  115 

state  in  which  these  find  themselves.  This  is  one  of  the 
reasons  why  certain  stains  when  injected  intravenously  are 
not  taken  up  with  the  same  speed,  or  to  the  same  extent,  by 
all  the  tissues  of  the  body. 

A  third  property  of  protoplasm,  which  makes  for  in- 
equalities in  the  distribution  of  a  substance,  resides  in  the 
chemical  differences  existing  between  different  kinds  of 
protoplasm.  Certain  of  the  ''  vital  "  and  "  specific  "  pro- 
toplasmic stains  are  examples  of  this  class.  In  these  a 
chemical  combination  results  between  the  dye  and  the 
chemical  compounds  found  in  some  cells. 

What  use  can  we  make  of  these  facts  in  the  explanation 
of  the  alterations  observed  in  the  secretion  of  dissolved 
substances  by  the  nephritic  kidney?  In  proposing  a  col- 
loidal theory  of  urinary  secretion,^  I  have  tried  to  show  how 
the  ^'  selective  "  character  of  secretion  may  be  explained  in 
the  following  way : 

All  secretion  of  dissolved  material  by  the  kidney  is  de- 
pendent, first  of  all,  upon  a  secretion  of  water  by  the 
kidney.  After  the  water  is  secreted  I  hold  that  all  the  con- 
stituents which  characterize  it  as  urine  come  to  be  added 
to  it,  in  its  course  through  the  uriniferous  tubules,  by  a 
process  of  leaching  out  of  the  dissolved  substances  present 
in  the  kidney  cells.  But  in  this  process  of  leaching  out  not 
all  the  constituents  present  in  the  protoplasm  leave  the 
cells  in  which  they  are  originally  present  with  the  same 
ease.  Depending  upon  the  character  of  the  dissolved  sub- 
stance, and  the  state  of  the  protoplasm  as  to  lipoid  content, 
colloidal  state,  and  chemical  composition,  the  water  pres- 
ent in  the  uriniferous  tubule  may  come  to  take  up  the  dis- 
solved substance  to  an  extent  which  allows  it  ultimately 
to  be  found  here  in  a  lower  concentration  than  in  the  kidney 
cells,  in  the  same  concentration,  or  in  a  greater  one.  It  is 
1  Martin  H.  Fischer:  (Edema,  180.    New  York,  1910. 


ii6  NEPHRITIS 

all  a  matter  of  equilibrium.  But  the  equilibrium  points 
with  different  substances  are  different,  and  so  the  relative 
amounts  of  these  different  substances  that  appear  in  the 
urine  are  also  different.  In  other  words,  the  (normal)  leach- 
ing out  is  ''  selective,"  or,  to  put  it  biologically,  the  ''  secre- 
tion "  of  the  dissolved  substances  is  selective. 

But  this  leaching  out  of  dissolved  substances  from  the 
kidney  is  only  one-half  of  the  process  of  urinary  secretion. 
The  other  half  is  the  process  of  the  absorption  of  dissolved 
substances  from  the  blood  by  the  kidney  cells  preparatory 
to  their  secretion  into  the  lumen  of  the  uriniferous  tubules. 
This  is  also  a  selective  process,  and  here  the  same  laws  of 
lipoid  solubility,  colloidal  adsorption,  and  chemical  combi- 
nation, which  have  already  been  discussed  in  the  leaching 
out  process,  again  come  into  play. 

All  these  various  processes  of  absorption  and  secretion  of 
dissolved  substances  by  the  kidney  cells  are  most  markedly  in- 
fltcenced  by  the  reaction  existing  in  them,  and  it  is  for  this 
reason  that  the  observed  variations  from  the  normal  in  the 
secretion  of  dissolved  substances  by  the  nephritic  kidney  occur. 

It  is  easily  appreciated  w^hy  there  must  be  a  decrease  in 
the  absolute  amount  of  dissolved  substance  secreted  by  the 
nephritic  kidney.  If  the  secretion  of  water  through  the 
kidney  is  diminished,  then  clearly  not  as  much  dissolved 
substance  can  be  leached  out  of  the  kidney  parenchyma  as 
when  more  is  secreted.  Into  this,  however,  enters  the  ele- 
ment of  time.  When  much  water  is  being  secreted  by  a 
kidney  its  discharge  into  the  pelvis  of  the  kidney  is  also 
hastened.  The  time  that  a  given  portion  of  the  urine 
(secreted  as  water  initially)  is  in  contact  with  the  kidney 
cells  is  thereby  diminished,  and  so  not  all  that  this  water 
is  capable  of  absorbing  is  taken  up.  When  the  water  is 
secreted  more  slowly,  the  ultimate  equihbrium  point  for 
the  distribution  of  dissolved  substances  between  the  kidney 


1 


NEPHRITIS 


119 


and  the  urine  is  more  nearly  approximated.  We  find  daily 
expression  of  this  fact  in  the  clinical  observation  that  after 
the  consumption  of  much  water  the  concentration  of  the 
urine  falls,  while  with  a  diminished  intake  of  water,  or 
when  the  kidney  cannot  secrete  it  (as  in  nephritis),  the  con- 
centration of  the  urine  becomes  progressively  higher.  Yet, 
other  things  being  equal,  the  absolute  amount  of  any  dis- 
solved substance  secreted  by  the  kidney  must  be  the  greater, 
the  larger  the  absolute  amount  of  water  secreted  by  the 
kidney  in  any  unit  of  time. 

To  illustrate  how  the  increased  acid  content  in  the 
kidney  in  nephritis  leads  to  variations  in  the  secretion  of 
the  dissolved  substances,  I  would  like  to  introduce  a  few 
simple  test-tube  experiments  and  experiments  on  rabbits, 
which  concern  themselves  particularly  with  that  part  of 
the  selective  secretion  which  deals  with  the  colloidal  state 
of  the  kidney  cells.  This  constitutes  by  far  the  most  im- 
portant part  of  the  whole  problem  of  selective  absorption 
and  secretion,  for  the  state  of  a  colloid  in  the  body  is  more 
easily  affected  by  external  conditions  than  is  the  solvent 
property  of  a  lipoid,  or  the  chemical  character  of  any  part 
of  living  protoplasm.  As  the  various  dyes  betray  them- 
selves not  only  qualitatively,  but,  in  a  sense,  also  quanti- 
tatively, to  the  naked  eye,  illustrations  of  the  "  absorption  " 
and  the  "  secretion  "  of  these,  under  conditions  that  interest 
us  in  our  discussion  of  nephritis,  seemed  to  me  best  suited 
to  our  needs.  I  chose,  moreover,  dyes  that  have  been  used 
physiologically  in  the  study  of  the  kidney.  The  results 
of  a  few  experiments  on  the  staining  of  fibrin,  which  are 
familiar  to  any  worker  who  has  at  all  touched  upon  the 
problem  of  dyeing,  and  which  might  be  multiplied  indefi- 
nitely by  using  other  dyes  and  different  colloids,  are  shown 
in  Fig.  21. 

Tube  I  contains  an  aqueous  solution  of  toluidin  blue. 


120  NEPHRITIS 

If  into  another  tube  (2),  containing  the  dye  in  the  same 
concentration,  some  powdered  fibrin  is  dropped,  this  soon 
absorbs  most  of  the  dye  and  stains  intensely  blue.  The 
supernatant  Hquid  retains  only  a  faint  tinge  of  the  blue 
but  this  remains  indefinitely.  If  the  supernatant  solution 
is  carefully  pipetted  off,  and  distilled  water  is  placed  over 
the  dyed  fibrin,  the  water  now  slowly  turns  blue.  In 
this  way,  through  successive  washings,  we  can  again  get 
considerable  of  the  blue  out  of  the  fibrin.  In  other  words, 
the  fibrin  absorbs  the  dye  until  an  equilibrium  is  reached 
between  the  concentration  of  the  dye  in  the  fibrin  and  the 
concentration  of  the  dye  dissolved  in  the  supernatant 
liquid.  If  now  wt  disturb  this  equilibrium  by  removing 
the  blue  solution  above  the  fibrin  and  substituting  water 
for  it,  some  of  the  dye  comes  out  of  the  fibrin  until  equiHb- 
rium  is  once  more  established. 

If  we  will  now  write  kidney  coUoids  for  fibrin  we  have 
what  happens  in  this  organ  when  it  secretes  any  dye. 
The  absorption  of  the  dye  by  the  kidney  cells  from  the 
blood  is  analogous  to  the  first  series  of  changes  that  we 
describe,  the  leaching  out  of  the  dye  by  the  urine  to  the 
second  series.  We  can  also  see  at  once  why  the  quantity 
of  urine  secreted  and  the  time  that  this  remains  in  contact 
with  the  kidney  cells  are  of  such  importance.  This  cor- 
responds with  the  renewal  of  the  distilled  water  above  the 
dyed  fibrin  and  the  time  this  is  allowed  to  remain  there 
before  being  pipetted  off. 

What  happens  if  we  introduce  into  this  w^hole  system  a 
trace  of  acid?  The  result  is  shown  in  tube  3.  The  fibrin 
swells  somewhat,  but  the  toluidin  blue  is  now  scarcely 
taken  up.  The  supernatant  liquid  remains  practically  as 
blue  as  the  control  tube  i.  What  would  this  mean  when 
applied  to  the  kidney  affected  with  nephritis,  for  which  we 
have  maintained  that  an  abnormal  acid  content  is  respon- 


NEPHRITIS  121 

sible?  That  the  kidney  would  swell  as  does  the  fibrin, 
with  this  we  are  already  familiar.  But  such  a  kidney 
would  now  not  absorb  the  toluidin  blue  preparatory  for 
secretion  as  does  the  healthy  kidney.  On  the  other  hand, 
we  must  not  hastily  conclude  herefrom  that  under  such 
circumstances  the  kidney  would  necessarily  also  secrete  this 
dye  badly.  Once  any  dye  was  in  the  kidney  colloids  this 
would  rapidly  diffuse  into  the  urine,  not  only  because  the 
kidney  colloids  are  not  holding  on  to  the  dye  particularly 
firmly,  but  because  the  acid  Hable  to  be  in  such  urine  as  is 
secreted  from  the  nephritic  kidney  would  further  favor  the 
passage  of  the  dye  into  it. 

In  tubes  4,  5,  and  6  are  shown  a  parallel  series  of  experi- 
ments carried  out  with  sodium  indigosulphonate.  It  is 
clear  that  with  this  dye  conditions  are  exactly  the  reverse 
of  those  obtaining  in  the  case  of  toluidin  blue.  The  very 
circumstances  which  favored  absorption  before,  hinder  it 
here,  and  those  which  hindered  it  before  now  favor  it.  In 
tubes  7,  8,  and  9  are  shown  the  results  obtainable  with 
neutral  red,  which,  it  will  be  observed,  behaves  like  toluidin 
blue. 

But  the  kidney  is  not  thus  offered  one  substance  at  a 
time  to  secrete  into  the  urine.  The  blood  that  passes 
through  this  organ  brings  it  many  at  once.  What  must  be 
the  behavior  of  the  tissue  colloids  under  such  circumstances? 
As  tubes  10,  II,  and  12,  and  tubes  13,  14,  and  15  clearly 
show,  a  colloid  under  such  circumstances  behaves  toward 
each  of  the  substances  offered  it  as  though  the  others  were 
not  present.  In  tube  10  is  shown  the  effect  of  mixing  so- 
dium indigosulphonate  and  neutral  red.  If  some  fibrin  is 
introduced  into  this  mixture  it  absorbs  the  red  (chiefly)  and 
leaves  behind  (almost)  all  the  blue.  This  would  correspond 
with  the  kidney  function  in  health.  If  now  an  abnormal 
amount  of  acid   were  present  in   the  kidney  (nephritis) 


122  NEPHRITIS 

just  the  reverse  would  result  —  the  red  would  now  be  left 
behind  in  the  blood,  while  the  blue  would  be  absorbed. 

In  tubes  13,  14,  and  15  are  shown  the  results  on  "the 
staining  of  fibrin  when  toluidin  blue  and  neutral  red  are 
mixed.  The  resulting  color  is  shown  in  tube  13.  In  the 
presence  of  fibrin  both  of  the  dyes  are  absorbed  as  shown 
in  tube  14,  but  if  a  Httle  acid  is  present,  or  is  subsequently 
added,  the  fibrin  fails  to  stain.  Figure  21  was  painted  from 
the  results  obtained  in  the  following  Experiment  21,  after 
the  tubes  had  stood  some  eighteen  hours.  Marked  differ- 
ences in  the  degree  of  staining  are  readily  visible,  however, 
after  ten  minutes. 

Experiment  21. 

1.  15  c.c.  .01  per  cent  toluidin  blue  plus  15  c.c.  water. 

2.  15  c.c.  .01  per  cent  toluidin  blue  plus  15  c.c.  water  plus  0.4 
gram  fibrin. 

3.  15  c.c.  .01  per  cent  toluidin  blue  plus  15  c.c.  ^V  normal  acetic 
acid  plus  0.4  gram  fibrin. 

4.  15  c.c.  .02  per  cent  sodium  indigosulphonate  plus  15  c.c.  water. 

5.  15  c.c.  .02  per  cent  sodium  indigosulphonate  plus  15  c.c.  water 
plus  0.4  gram  fibrin. 

6.  15  c.c.  .02  per  cent  sodium  indigosulphonate  plus  15  c.c.  ^tf 
normal  acetic  acid  plus  0.4  gram  fibrin. 

7.  15  c.c.  .02  per  cent  neutral  red  plus  15  c.c.  w^ater. 

8.  15  c.c.  .02  per  cent  neutral  red  plus  15  c.c.  water  plus  0.4  gram 
fibrin. 

9.  15  c.c.  .02  per  cent  neutral  red  plus  15  c.c.  2V  normal  acetic 
acid  plus  0.4  gram  fibrin. 

10.  15  c.c.  .02  per  cent  sodium  indigosulphonate  plus  15  c.c.  .02 
per  cent  neutral  red. 

11.  15  c.c.  .02  per  cent  sodium  indigosulphonate  plus  15  c.c.  .02 
per  cent  neutral  red  plus  0.4  gram  fibrin. 

12.  7I  c.c.  .04  per  cent  sodium  indigosulphonate  plus  7!  c.c.  .04 
per  cent  neutral  red  plus  15  c.c.  2V  normal  acetic  acid  plus  0.4  gram 
fibrin. 

13.  15  c.c.  .01  per  cent  toluidin  blue  plus  15  c.c.  .02  per  cent 
neutral  red. 


NEPHRITIS  123 

14.  15  c.c.  .01  per  cent  toluidin  blue  plus  15  c.c.  .02  per  cent 
neutral  red  plus  0.4  gram  fibrin. 

15.  7I  c.c.  .02  per  cent  toluidin  blue  plus  ^7^  c.c.  .04  per  cent 
neutral  red  plus  15  c.c.  ^V  normal  acetic  acid  plus  0.4  gram  fibrin. 

The  details  of  this  experiment  have  already  been  discussed  in  the 
text. 

It  follows  from  all  this  that  the  presence  of  a  little  acid 
in  such  a  colloidal  material  as  that  which  we  know  to  com- 
pose the  kidney  must  be  followed  by  profound  changes  in 
the  character  of  the  secretion  of  dissolved  substances  by 
this  organ  as  compared  with  the  normal  secretion  of  these 
same  substances.  But  depending  upon  the  way  in  which 
the  acid  displaces  the  equilibrium  point  it  is  clear  that, 
with  otherwise  constant  conditions,  the  secretion  of  any 
substance  may  not  only  be  decreased  or  simply  remain 
unaffected,  but  it  may  actually  be  increased.  With  illus- 
trations of  the  first  two  of  these  possibilities  we  are  familiar 
from  the  analyses  of  the  urine  in  nephritis.  Examples  of 
the  third  have  not  yet  been  sought  for. 

Before  closing  this  chapter  it  is  well  to  refer  to  a  few 
animal  experiments  which  show  that  what  has  been  said 
above  regarding  the  staining  of  fibrin  actually  holds  in 
the  case  of  the  living  animal.  As  pointed  out  in  our 
discussion  of  the  experiments  of  Heidenhain,  Dreser,  and 
Nussbaum,  these  authors  found  the  kidneys  of  their  ex- 
perimental animals  stained  most  deeply,  and  most  generally 
with  sodium  indigosulphonate  or  acid  fuchsin  (which  stains 
fibrin  just  as  does  sodium  indigosulphonate)  when  con- 
ditions favoring  the  accumulation  of  acid  in  the  kidney 
were  most  clearly  at  hand.  This  corresponds  with  the  im- 
proved tendency  of  fibrin  to  stain  with  these  dyes  when 
an  acid  is  present.  When  in  a  rabbit  under  morphine  an- 
esthesia the  artery  to  one  kidney  is  clamped  for  an  hour  or 
two,  and  then  sodium  indigosulphonate  or  acid  fuchsin  is 


124 


NEPHRITIS 


injected  intravenously,  while  the  clamp  is  removed  from 
the  artery,  it  is  found  that  tJie  clamped  kidney  not  only 
stains  sooner  than  the  undamped  one,  hut  more  intensely. 
Wrhen  now  frozen  sections  are  made  of  the  two  kidneys  the 
dye  in  the  healthy  kidney  is  found  only  in  the  lumina  of  the 
uriniferous  tubules,  while  in  the  Hgated  kidney  it  is  found 
in  the  cells  themselves.  And  yet  a  kidney  so  clamped  for 
an  hour  or  two  will  not  yield  any  urine  for  hours  after- 
wards, if  ever  again.  The  staining  of  the  kidney^  as  already 
once  noted  above,  is  therefore  not  an  index  of  secretion,  but  in 
this  case  rather  of  its  lack. 

The  reverse  of  this  experiment  can  be  done  with  neutral 
red.  Here  the  normal  kidney  stains  well  and  rapidly, 
while  the  clamped  one  remains  without  color,  owing  to  the 
acid  developed  in  it  in  the  absence  of  a  circulation.  Clearly, 
therefore,  mere  staining  of  a  cell  can  by  itself  tell  us  Uttle 
regarding  the  secretion  of  such  a  stain  by  that  cell. 

After  what  has  been  said  it  must  be  self-evident  that  too 
many  factors  enter  into  the  picture  of  the  secretion  of  any 
dissolved  substances  by  the  kidney  —  too  many  factors  at 
which  we  can  to-day  but  guess  in  a  clinical  case  —  to  make 
any  conclusions  regarding  the  functional  activity  of  the 
kidney,  as  derived  from  a  study  of  the  ehmination  of  some 
one  compound  swallowed  by  the  patient  and  sought  for  in 
his  urine,  of  any  material  value.  Even  though  we  ignore 
all  other  elements  of  error,  the  state  of  the  blood,  the  state 
of  the  kidney  colloids,  and  the  state  of  the  urine  all  in- 
fluence the  rapidity  and  perfection  of  the  elimination  of  the 
substance  in  so  marked  and  (for  us)  uncontrollable  a  way, 
that  trustworthy  conclusions  are  impossible,  and  when  we 
take  the  Hberty,  as  is  so  often  done,  of  applying  what  we 
may  have  learned  from  the  elimination  of  one  substance 
without  modification  to  some  other  or  all  other  constitu- 
ents found  in  the  urine,  then  we  are  on  dangerous  ground 


NEPHRITIS 


125 


indeed.  Until  we  have  learned  far  more  regarding  the  laws 
that  govern  the  secretion  of  dissolved  substances  by  the 
kidney  than  we  know  to-day,  we  had  best  accept  as  the  most 
reliable  test  for  the  Junctional  activity  of  this  organ  its  ability 
to  eliminate  water. 

IV.     ON   THE   TREATMENT   OF   NEPHRITIS. 

For  the  treatment  of  nephritis  everything  has  been  sug- 
gested; a  discussion  of  the  subject  can  scarcely,  therefore, 
hope  to  bring  the  mention  of  anything  new  that  might  be 
tried.  It  can  hope  to  be  of  interest  or  importance  only  as 
on  the  basis  of  the  views  entertained  by  an  author  regard- 
ing the  nature  and  the  cause  of  nephritis  he  will  assign  to 
certain  practices  grades  of  importance  different  from  those 
assigned  to  these  same  practices  by  another  —  a  difference 
of  opinion  that  may  perhaps  be  carried  to  the  point  where 
the  one  will  find  virtue  in  procedures  that  another  regards 
only  as  evil,  and  vice  versa.  It  is  not  our  purpose  in  these 
pages  to  discuss  the  whole  question  of  the  therapeutics  of 
nephritis,  but  on  the  basis  of  what  has  been  written  we 
may  advantageously  take  up  a  few  points  in  this  field.  In 
so  doing  we  will  discover  further  support  for  the  concep- 
tion of  nephritis  that  has  been  advanced  in  the  preceding 
pages. 

I.   Some  General  Considerations. 

Were  we  to  formulate  a  general  rule  for  the  prophylaxis 
and  for  the  treatment  of  nephritis  we  would  evidently  have 
to  say  that  this  lies  in  an  avoidance,  as  far  as  possible,  of 
every  condition  that  favors  the  abnormal  production  or  ac- 
cumulation of  acid  in  the  kidney.  What  such  a  rule  would 
mean  in  the  language  of  every  day  is  easily  seen. 

We  have  long  paid  attention  to  the  diet  in  this  matter  of 
nephritis.  Clearly,  the  direct  consumption  of  acid  by  the 
nephritic  individual  is  contraindicated.    The  mineral  acids 


126  NEPHRITIS 

which  would  be  worst  in  this  regard  do  not  enter  into  our 
foods  to  any  appreciable  extent,  though  in  the  forms  of 
fruits,  sour  wines,  etc.,  not  inconsiderable  amounts  of 
organic  acids  are  swallowed.  Most  of  these  undergo  oxi- 
dation in  the  body  rather  easily  and  are  converted  into  car- 
bonic acid  which,  imder  ordinary  circumstances,  is  readily 
excreted.  The  organic  acids  are  therefore  less  poisonous 
than  might  at  first  appear,  but  from  this  is  not  to  be  con- 
cluded that  they  are  of  no  importance  at  all  in  the  con- 
sideration of  this  subject  of  nephritis.  Not  only  are  certain 
"  weak  "  organic  acids  (notably  tartaric,  acetic,  and  lactic) 
quite  as  active  physiologically  as  the  "  stronger  "  acids,  but 
consumed  in  excessive  amounts  they  are  not  without  effect, 
as  witness  the  oedema  observed  in  children  that  are  fed 
buttermilk,^  the  urticarias  following  the  consumption  of 
excessive  amounts  of  grapes, ^  etc. 

In  the  metabolism  of  proteins  not  inconsiderable  amounts 
of  acid  are  produced.^  Herein  is  to  be  sought  at  least  part 
of  the  explanation  of  why  a  restriction  of  the  proteins  in 
nephritis  is  of  use.  The  fats  also  yield  acids  when  digested 
and  so  may  the  carbohydrates  under  certain  circumstances. 
But  before  one  proceeds  to  a  too  drastic  rex-ision  of  the 
dietary,  a  process  in  which  we  are  particularly  Kable  to  elimi- 
nate the  proteins  too  vigorously,  the  absolute  amounts  of 
acid  formed  by  the  various  constituents  of  the  food  should 
be  considered.     When  this  is  done  it  will  be  found  that  the 

"^  Ernst  Scldoss:  Deut.  med.  Wochenschr.,  No.  22.  (1910).  Schloss  does 
not,  however,  consider  this  an  oedema  due  to  feeding  acid,  but  as  "  idio- 
pathic."    He  found  it  to  disappear  on  administering  calcium  salts. 

2  Personal  observation.  The  urticaria  disappears  as  soon  as  calcium  salts 
are  given,  or  fails  to  appear  entirely  if  such  are  consumed  with  the  grapes. 

3  G.  von  Bunge:  Zeitschr.  f.  Biol.,  10,  iii  (1874);  N.  Liinin:  Zeitschr.  f. 
physiol.  Chem.,  5,  31  (1881);  Emil  Ahdcrhalden:  Biochem.  Zentralbl.,  2,  257 
(1904).  See  also  the  important  studies  on  the  balance  of  acid-forming  and 
base-forming  elements  in  food  by  H.  C.  Sherman  and  A.  0.  GeUler:  Proc. 
Soc.  Exp.  Biol,  and  Med.  8.  119  (1911). 


NEPHRITIS 


127 


evil  consequences  expressed  in  terms  of  a  direct  acid  yield 
from  the  proteins  of  our  food,  for  example,  are  small  com- 
pared with  those  that  may  be  calculated  from  a  bottle  of 
dry  wine.  Consideration  of  the  acid  content  of  alcoholic 
beverages  helps  us  moreover  to  understand  why  some  of 
these  exercise  a  worse  effect  in  nephritis  than  others.  We 
have  long  recognized  that  the  alcohol  content  is  not  alone 
responsible  for  the  effects  of  alcoholic  beverages  in  kidney 
disease,  for  while  it  is  true  that  in  large  doses  alcohol  alKes 
itself  with  the  general  anaesthetics,  small  doses  do  not  in- 
terfere with  the  oxidative  reactions  in  the  living  cells,  but 
rather  favor  these  (and  so  kidney  function).  But  what- 
ever is  fed,  it  is  clear  that  all  the  acid  effects  of  the  food 
need  not  appear  if  we  will  take  the  precaution  of  seeing 
that  the  diet  contains  sufficient  alkali  to  neutrahze  the  acid. 
The  role  of  hard  work  as  a  factor  in  inducing  nephritis,  or 
aggravating  an  already  existing  one  has  been  too  long 
recognized  to  demand  any  special  comment.  Muscular 
work  and,  less  obviously,  mental  work  lead  to  an  enormous 
acid  production  in  the  body.  Sufficiently  hard  work  makes 
any  man  show  all  the  symptoms  and  signs  of  a  nephritis. 
Under  normal  circumstances  the  acids  produced  in  muscu- 
lar or  mental  endeavor  are  quickly  oxidized  and  leave  the 
body  in  the  form  of  carbon  dioxide.  But  for  this  a  plenti- 
ful oxygen  supply  is  demanded,  and  when  this  is  not  fur- 
nished, as  in  close  rooms  and  factories,  then  such  conditions 
become  factors  in  our  problem  of  nephritis.  Let  now  an 
anaemia^  be  added  and  we  have  built  out  of  a  few  circum- 

^  A  satisfactory  explanation  of  why  an  anaemia  is  so  often  associated  with 
nephritis  has  not  yet  been  given.  The  anaemia  is  a  prominent  sign  only  in 
the  parenchymatous  types  of  nephritis  —  those  that  have  an  oedema. 
This,  it  seems  to  me,  is  not  an  accidental  combination.  May  we  not  regard 
the  acid  which  yields  the  kidney  changes  and  which  is  to  be  held  responsible 
for  the  oedema  of  the  tissues  generally  also  responsible  for  the  anaemia,  in 
that  it  behaves  like  a  "  haemolytic  "  agent?  See  my  remarks  on  the  nature  of 
haemolysis  [Kolloid  Zeitschr.  5, 146  (1909)  or  (Edema,  166  (New  York,  1910)]. 


128  NEPHRITIS 

stances,  each  simple  enough  in  itself,  a  vicious  circle  that  has 
in  it  all  the  possibilities  of  speedy  death.  How  a  heart 
lesion,  or  an  ansesthetic,  or  a  drinking  bout,  or  exposure  to 
cold  may  push  the  acid  content  of  the  kidney  up  to  the 
point  where  it  can  care  for  it  no  longer  is  self  apparent. 

Just  as  we  have  seen  how  certain  circumstances  favor  the 
development  of  a  nephritis  so  also  can  we  see  how  others 
counteract  this.  Most  notable  here  are  the  long  observed 
beneficent  effects  that  follow  the  use  of  alkalies  and  the 
substitution  of  a  more  strictly  vegetarian  diet  for  our  ordi- 
nary mixed  diet.  The  alkaline  mineral  waters  are  of  course 
capable  of  pushing  the  equihbrium  existing  in  the  kidney 
between  the  hydrogen  ions  and  the  hydroxyl  ions  toward  the 
hydroxyl  side,  and  so  of  counteracting  that  rise  in  acidity 
here  which  we  consider  Kes  at  the  bottom  of  nephritis. 

A  diet  rich  in  vegetables  helps  our  nephritic  in  part  in 
the  same  way  as  though  he  consumed  alkalies  directly. 
The  bases  present  in  vegetables  are  combined  with  weak 
organic  acids;  in  other  words,  the  vegetables  contain  salts 
which  when  dissolved  in  water  are  alkaline  in  reaction.  In 
the  body  these  organic  acids  are  largely  oxidized  to  car- 
bonates and  so  the  tendency  of  the  body  tissues  to  become 
alkahne  in  reaction  is  still  further  developed.  How  suc- 
cessfully a  diet  rich  in  fruits  and  vegetables  counteracts 
even  the  normal  tendency  of  the  body  to  become  acid  is  a 
matter  of  common  knowledge  to  any  physician  who  has 
watched  the  urine  of  any  patient  turn  from  its  normal 
acidity  to  an  alkalinity,  when  ordered  from  an  ordinary 
mixed  diet  upon  one  richer  in  the  vegetables  and  fruits. 

But  I  would  like  to  insist  that  this  neutraHzation  capacity 
of  the  vegetable  diet  for  acids  is  not  the  only  factor  to  be 
considered  in  accounting  for  its  beneficent  effect  in  ne- 
phritis. We  learned  earHer  in  this  paper  that  the  solubiUty 
of  protein  in  any  acid  is  markedly  reduced  by  salts.    Not 


NEPHRITIS  129 

only  are  the  vegetables  rich  in  salts  but  they  are  rich  in  the 
very  ones  which  act  most  powerfully  in  reducing  the  solu- 
bihty  of  the  protein.  So  we  may  find  in  this  fact,  along 
with  what  has  already  been  said  regarding  the  capacity 
of  the  vegetable  diet  to  neutraHze  acids,  a  satisfactory 
scientific  foundation  for  the  reduction  of  the  albuminuria 
in  Bright' s  disease,  when  a  diet  rich  in  vegetables  follows 
one  in  which  these  were  not  so  abundant.  Such  salts  also 
serve  to  reduce  the  size  (swelHng)  of  the  kidney,  and  as 
we  have  seen,  they  practically  prevent  those  precipitation 
effects  in  the  kidney  cells  (granule  formation)  that  are 
characteristic  of  the  early  changes  of  nephritis  from  a  mor- 
phological point  of  view.  Speaking  generally,  a  diet  high 
in  vegetables  also  means  that  the  individual  is  consuming 
more  water.  The  effect  of  this  will  next  be  discussed,  and 
later  we  shall  return  once  more  to  the  question  of  salts  in 
the  diet. 

2.  Water  Consumption  in  Nephritis. 

The  question  of  water  consumption  resolves  itself  into 
two  parts,  on  the  one  hand,  into  the  use  of  water  in  cases 
where  a  nephritis  is  likely  to  arise,  on  the  other,  to  its  use 
in  an  established  case.  From  all  that  has  been  said  it 
must  be  clear  that  the  intake  of  water  should  never  be  re- 
stricted. To  this  rule  there  exists  to  my  mind  only  one 
possible  exception,  and  that  is  the  advisabihty  of  stopping 
water  temporarily  —  say  for  an  hour  or  two  for  reasons 
that  will  appear  later  —  in  cases  of  complete  suppression 
of  the  urine.  Neither  does  this  statement  mean  that  pure 
water  is  necessarily  the  best  form  in  which  to  take  this,  but 
with  this  matter  we  will  deal  immediately.  The  reasons 
why  water  should  be  given  without  restriction  are  obvious. 
No  matter  with  what  condition  we  are  dealing  that  we  may 
consider  liable  to  lead  to  a  nephritis,  what  produces  that 


I30  NEPHRITIS 

pathological  state  in  the  end  is  an  intoxication.  This  is 
strikingly  true  of  course  in  the  infectious  diseases  or  in  an 
eclampsia  case.  Here  the  whole  organism  is  suffering  from 
the  effects  of  a  poison.  The  effect  of  that  poison  depends 
not  alone  upon  the  length  of  time  that  it  acts  upon  the 
organism  as  a  whole  or  any  individual  part  of  it,  but  upon 
the  concentration  of  the  poison  present  at  any  one  time. 
If  now  our  interest  centers  upon  a  toxic  effect  that  such  a 
poison  may  have  upon  the  kidney,  and  we  are  anxious  to 
protect  this  organ,  it  is  clear  that  the  concentration  of  the 
poison  must  be  kept  as  low  as  possible  in  this  organ.  To 
do  this  we  have  only  two  possibiHties  open  to  us  and  when 
we  cannot  control  the  factor  of  poison  production,  we  can 
hope  to  cut  dow^n  the  eft'ect  of  the  poison  only  by  keeping 
what  is  produced  as  dilute  as  possible,  which  means  the 
giving  of  water.  In  this  connection  the  practical  point 
should  be  remembered  that  in  ordinary  practice  an  ever  so 
patient  administration  of  water  through  the  day  is  Hkely  to 
be  neglected  in  the  night.  As  toxine  production  does  not 
cease  wdth  nightfall,  it  is  clear  that  water  administration 
also  should  not,  otherwise  we  are  likely  to  lose  in  a  few 
hours  at  night  what  we  cannot  subsequently  regain  in  days, 
if  at  all. 

At  this  point  we  are  likely  to  be  met  by  the  argument 
that  while  such  a  water  therapy  is  accepted  as  advisable  in 
the  toxic  nephri tides,  those  associated  with  heart  lesions, 
etc.,  are  not  to  be  similarly  treated.  Let  us  first  point  out 
the  fact  that  these  too  are  toxic  nephritides  —  the  patient 
with  a  broken  heart  compensation,  or  a  compressed  lung 
due  to  a  carcinomatous  pleurisy,  and  albumin  in  his  urine 
shows  this  (according  to  our  views),  because  the  acid  con- 
tent in  his  kidneys  is  abnormally  high.  The  more  the  con- 
centration of  this  can  be  reduced  the  less  will  be  its  effect 
on  the  kidneys.     Thus  far,  therefore,  he  needs  water  quite 


NEPHRITIS  131 

as  much  as  the  nephritic  who  is  such  in  consequence  of  an 
infectious  disease. 

But  it  will  be  argued  that  the  giving  of  water  increases 
the  work  of  the  heart  in  these  cases,  and  so  is  bad.  Let 
us  consider  this  problem  dispassionately.  The  beHef  that 
the  giving  of  water  increases  the  work  of  the  heart  is  based 
upon  the  notions  of  urinary  secretion,  which  imagine  that 
water  is  pushed  through  the  kidney  cells  by  gross  mechani- 
cal means.  And  so  it  is  reasoned  that  the  more  water  that 
is  given,  the  more  push  is  required,  that  is  to  say,  the  more 
blood  pressure,  and  so  the  more  work  from  the  heart.  Actu- 
ally such  a  belief  lacks  every  experimental  support.  If  one 
fact  regarding  urinary  secretion  stands  out  as  well  estab- 
lished, it  is  that  the  forces  active  in  producing  the  urinary 
secretion  lie  within  the  kidney  itself.  The  only  thing  there- 
fore that  we  might  call  upon  as  responsible  for  increasing 
the  work  of  the  heart  would  be  some  product  of  the  work  of 
the  kidney  in  separating  urine  from  the  blood.  We  have  a 
right  to  consider  here  the  effect  on  the  heart  of  the  extra 
carbon  dioxide^  produced  whenever  the  kidney  functions. 
But  the  effect  of  this  cannot  be  greater  than  that  of  an  equal 
amount  produced  normally,  or  in  a  given  case  of  kidney 
disease  than  an  equal  amount  produced  in  some  other 
organ.  And  when  compared  with  the  total  amount  of 
carbon  dioxide  produced  from  all  other  sources,  the  amount 
of  carbon  dioxide  produced  in  the  kidney  because  of  the 
consumption  of  a  few  extra  hters  of  water  is  small  indeed. 

Even  were  we  to  admit  that  the  effect  of  such  an  increased 
carbon  dioxide  production  by  the  kidney  did  markedly  in- 
crease the  work  of  the  heart  —  a  view  for  which  we  have 
not  a  single  unequivocal  clinical  observation  —  it  would 
still  have  to  be  proved  that  such  an  effect  is  worse  than  that 

1  Barcroft  and  T.  G.  Brodie:  Journal  of  Physiology,  32,  18  (1904);  33,  52 
(1905)- 


132  NEPHRITIS 

resulting  from  an  accumulation  of  acid  in  the  kidney  (and 
in  the  body  generally)  because  of  an  insufficient  eKmination 
of  water  through  the  kidney.  As  a  matter  of  fact,  we 
know  this  reasoning  to  be  sound  from  the  fact  that  the 
parenchymatous  t^'pes  of  nephritis,  in  which  water  elimi- 
nation is  most  decidedly  insufficient,  and  in  which  it  would 
be  expected  in  consequence  that  the  heart  would  be  work- 
ing hardest  in  order  to  rid  the  body  of  any  consumed  water, 
are  the  very  types  in  which  heart  complications  (hyper- 
trophy) are  most  conspicuously  absent. 

Let  us  now  ask  if  in  the  chronic  interstitial  types  of  ne- 
phritis this  rule  of  no  water  restriction  also  holds  good. 
We  have  sufiiciently  dilated  upon  the  fact  that  chronic  in- 
terstitial nephritis  without  urinary  findings  is  not  physio- 
logically a  nephritis.  When  albumin,  casts,  and  oedema 
appear,  that  which  we  have  just  said  for  parenchymatous 
nephritis  holds  for  it.  But  what  is  to  be  our  position  when 
the  urinary  findings  are  absent? 

As  we  have  already  pointed  out,  the  work  done  by  the 
heart  in  pumping  blood  through  the  blood  vessels  depends 
upon  the  length,  diameter,  and  elasticity  of  the  blood  vessels, 
and  upon  the  viscosity  of  the  blood.  The  giving  of  water 
certainly  does  not  affect  the  first  three  factors.  So  far  as 
viscosity  is  concerned,  it  can  only  decrease  this  and  so  dimin- 
ish the  work  of  the  heart,  as  diluting  a  syrup  with  water 
makes  it  easier  to  draw  it  through  a  straw.  If  we  are  will- 
ing to  admit  that  in  consequence  of  the  general  circulatory 
disturbances  in  our  patient  with  chronic  interstitial  ne- 
phritis the  increased  work  thrown  upon  his  heart  is  in  part 
due  to  an  increase  in  the  viscosity  of  his  blood  occasioned 
by  the  presence  of  abnormal  amounts  of  acid  in  it,  then 
the  giving  of  water  must  again  be  of  help,  for  this  aids  in 
decreasing  the  concentration  of  the  acid. 

The  only  objections  that  may  be  raised  against  a  too 


NEPHRITIS  133 

vigorous  administration  of  water,  it  seems  to  me,  are  two. 
The  first  is  associated  with  the  fact  that  in  the  parenchyma- 
tous types  of  kidney  disease  the  kidney  swells;  the  second 
with  the  effect  of  the  water  in  washing  out  salts.  We  have 
already  said  why  the  swelling  occurs  in  nephritis  —  the 
abnormal  acid  content  of  the  kidney  cells  increases  the 
capacity  of  their  colloids  for  water,  and  consequently  if 
this  is  offered  them  they  swell.  And  so  it  might  be  reasoned 
that  to  give  water  in  the  acuter  forms  of  nephritis  would  be 
to  aid  this  swelhng.  Such  swelling  of  the  cells,  so  far  as 
the  cells  themselves  are  concerned,  can  hardly  be  considered 
serious,  any  more  than  a  moderate  oedema  of  any  tissue  is 
in  itself  particularly  destructive  to  the  tissue.  But  in  the 
case  of  the  kidney  a  complicating  circumstance  arises  which 
does  make  such  a  swelHng  dangerous.  This  resides  in  the 
fact  that  the  capsule  of  the  kidney  is  not  as  expansible  as 
the  rest  of  the  kidney  substance.  As  the  kidney  substance 
swells  this  tends,  therefore,  to  press  upon  the  blood  vessels 
and  retard  the  circulation  of  the  blood  through  the  kidney. 
This  condition  actually  comes  to  pass  in  the  acuter  forms  of 
nephritis.  The  kidney  already  nephritic,  say  from  the  tox- 
ine  of  an  infectious  disease  or  an  anaesthetic,  tends  to  make 
itself  worse  by  thus  hampering  its  blood  flow. 

The  washing  out  of  salts  from  the  kidney  acts  in  the  same 
general  direction,  for,  as  already  noted,  the  presence  of  salts 
tends  to  counteract  the  effects  of  acids  in  producing  swell- 
ing of  the  (hydrophiHc)  emulsion  colloids  of  the  kidney. 
Our  problem  might,  therefore,  seem  to  become  that  of  bal- 
ancing the  good  effects  of  water  against  certain  bad  ones. 
Actually  the  problem  is  much  simpler.  A  kidney  that  is 
killing  itself  clearly  needs  water  to  rid  itself  of  the  poisons 
that  are  killing  it  and  so,  from  this  point  of  view,  water  is 
indicated.  We  can  give  the  kidney  the  benefit  of  these  virtues 
of  the  water,  while  we  protect  it  at  the  same  time  from  the 


134  NEPHRITIS 

dangers  associated  with  the  water  by  giving  along  with  the 
water  certain  salts.  To  a  consideration  of  this  subject  we 
will  now  turn. 

3.  The  Role  of  Salts  in  the  Relief  of  Nephritis. 

We  have  labored  thus  far  to  show  how  a  parallelism  ex- 
ists between  the  changes  that  various  colloids  undergo  in 
the  presence  of  any  acid  and  the  changes  that  are  observed 
in  the  kidney  when  this  becomes  the  seat  of  a  nephritis. 
We  have  noted  how  the  swelHng  of  the  kidney  in  nephritis 
is  like  the  sweUing  of  fibrin  or  gelatine  in  water  when  a 
little  acid  is  added  to  this;  how  under  the  same  circum- 
stances some  of  the  colloids  go  into  solution,  and  so  the 
development  of  an  albuminuria  is  simulated;  how  when  a 
colloid  of  the  nature  of  casein  is  mixed  with  these,  this  is 
precipitated  under  conditions  which  make  the  others  swell, 
thus  behaving  Hke  certain  granules  observed  to  arise  in 
the  cells  of  the  kidney  under  conditions  associated  with  a 
nephritis. 

In  studying  the  behavior  of  the  pure  colloids  we  learned 
more  than  this.  We  learned,  first  of  all,  that  the  swelling 
of  the  colloids  could  be  reduced,  not  only  by  neutralizing  the 
acid,  but  by  adding  to  the  acid  any  neutral  salt.  So  far  as 
the  precipitation  of  casein  was  concerned  the  salts  divided 
themselves  into  two  groups  —  the  one  added  itself  to  the 
effect  of  the  acid  and  favored  precipitation,  the  other 
counteracted  such  an  effect.  If  now  our  contention  is 
correct  that  the  series  of  changes  observed  in  these  simple 
colloids  and  in  the  kidney  are  identical  in  character,  then 
it  was  to  be  expected  that  the  administration  of  properly 
selected  salts  should  relieve  the  various  signs  characteristic  of 
a  fiephritis.  That  such  is  in  fact  the  case  is  shown  by  the 
experiments  that  follow. 

The  choice  of  salts  for  these  experiments  was  not  an 


NEPHRITIS  135 

arbitrary  one,  and  what  would  constitute  an  ideal  salt  for 
the  relief  of  nephritis  could  well  be  told  in  advance.  Clearly, 
no  salt  which,  when  employed  in  the  concentrations  and 
amounts  necessary  to  get  the  desired  effects,  had  any 
"specific"  poisonous  action  upon  the  experimental  animal  or 
human  being  was  of  any  use.  Beyond  this  it  was  necessary 
to  find  one  which  combined  a  maximum  of  those  effects 
which  tended  on  the  whole  to  help  the  nephritis  (reduction 
of  protein  solubihty  and  swelling  of  the  kidney)  with  a 
minimum  of  those  which  aggravated  such  a  condition  (aug- 
mentation of  protein  precipitation  in  the  cells).  As  part 
of  the  relief  of  a  nephritis  centers  in  the  neutralization  of 
acid,  a  salt  capable  of  combining  with  such  clearly  possesses 
certain  advantages.  For  this  reason  such  salts  as  are  the 
combination  of  a  weak  acid  with  a  strong  base,  as  the 
phosphates,  citrates,  tartrates,  and  malates  of  sodium  at 
once  suggest  themselves.  But  neutral  salts  are  also  effec- 
tive in  reducing  the  solution  and  the  swelling  of  such  emul- 
sion colloids  as  fibrin,  gelatine,  and  serum  albumin  and  so 
the  use  of  the  chlorides  and  sulphates  of  sodium,  potassium, 
and  magnesium  suggests  itself.  But  which  of  these  salts 
may,  or  can  in  the  end,  be  employed  depends  upon  how 
urgently  we  wish  to  use  them  to  get  our  effects,  or  how 
much  of  them  we  wish  to  give  at  one  time,  and  the  mode  of 
administration  employed.  The  citrates  which,  on  theo- 
retical grounds,  one  is  tempted  to  use  cannot  be  given  in- 
travenously in  sufficient  amounts  to  prove  useful,  though 
administration  through  the  alimentary  tract  renders  them 
safe.  And  this  explains  why  when  we  come  to  use  these 
salts  clinically  our  hst  becomes  comparatively  short,  and, 
for  intravenous  injection,  very  short  indeed. 

As  our  argument  thus  far  has  seemed  to  indicate  to  us 
that  all  the  signs  of  a  nephritis  are  referable  to  a  single 
underlying  cause,  so  of  course  we  would  expect  that  did  we 


136  NEPHRITIS 

succeed  in  discovering  any  means  of  combating  this  cause 
all  the  signs  of  the  nephritis  would  disappear  en  masse. 
Such  is  as  a  matter  of  fact  the  case,  though  to  show  the 
salutary  action  of  the  various  procedures  employed  their 
effect  on  the  various  signs  has  been  studied  separately. 

§1. 

In  order  to  show  that  salts  inhibit  the  development  of  the 
signs  of  a  nephritis  it  was  necessary,  first  of  all,  to  decide 
upon  satisfactory  methods  of  producing  a  nephritis  experi- 
mentally in  animals,  upon  which  might  then  be  tried  the 
action  of  various  salts.  Three  different  methods  of  pro- 
ducing the  nephritis  were  employed:  interference  with  the 
respiration  of  the  animal,  the  intravenous  injection  of 
acid,  and  direct  clamping  of  the  renal  blood  vessels.  Of 
all  these  the  last  named  is  probably  grossest  in  its  effects 
upon  the  kidney.  For  the  sake  of  comparison  the  pro- 
tocols of  the  experiments  on  the  animals  which  served  as 
controls  have  been  inserted  in  each  case. 

Let  us  turn  first  to  a  consideration  of  the  nephritis  that 
develops  in  rabbits,  when  these  are  tied  into  the  animal 
holder  sufficiently  tight  to  interfere  with  their  respiration. 
One  always  gets  an  albuminuria  after  such  a  procedure  as 
the  following  protocols  show: 


NEPHRITIS 


137 


Experiment  22.  —  White  rabbit;  weight  898  grams.  Fed  wheat 
and  grass.  Snugly  tied  into  holder.  Urine  obtained  with  a  soft 
rubber  catheter. 


Time. 

Urine 
in  c.c. 

Remarks. 

3-00 

Bound  into  holder. 

3-30 

3-7 

Alkaline  to  litmus  paper.     No  albumin. 

3-45 

5.0  { 

Clearer  urine.  Neutral  to  litmus  paper.  Trace 
of  albumin. 

4.00 

3.0    1 

Clear  urine.  Neutral  to  litmus.  Albumin 
present. 

41S 

1.8  ^ 
0.9 
I.I     J> 

1-5 
1.8  J 

4.30 
4.45 
5  00 

Clear.     Neutral  to  litmus.     Albumin  present  in 

every  sample,  and  increasing  in  amount. 

515 

S.16 

Animal  seems  entirely  well.     Returned  to  hutch. 

Experiment  2^.  —  Belgian  hare;  weight  1226  grams.  Fed  wheat 
and  grass.  Snugly  tied  into  holder.  Urine  obtained  with  a  soft 
rubber  catheter. 


Time. 

Urine 
in  c.c. 

Remarks. 

2.45 

Few  drops' 
1 .0 

0.5    ' 

Few  drops  J 

3 
3 

00 
15 

Alkaline,  thick,  chrome  yellow.    No  albumin. 

3 

30 

3 

4=; 

Few  drops 

Neutral  and  clearer.     Trace  of  albumin. 

4 

00 

Few  drops"! 

4 

I"? 

Few  drops 

4 

4'> 

2.0        ^ 

Neutral  and  clearer.    Albumin  present. 

5 

00 

Few  drops 

5 

IS 

Few  drops  ^ 

5 

16 

Animal  released  and  returned  to  hutch. 

138 


NEPHRITIS 


Experiment  24.  —  Belgian  hare;  weight  1020  grams.  Fed  wheat 
and  grass.  Snugly  tied  into  animal  holder.  Urine  obtained  with  a 
soft  rubber  catheter. 


Time. 

Urine 
inc.c. 

Remarks. 

3-30 

30 

1 

3-45 

0.7 

1 

Tied  down.     Turbid,  dark  yellow.     Alkaline 

4.00 

05 

r 

to  litmus.     No  albumin. 

4-15 

Few  drops  J 

1 

Turbid,  dark  yellow,  alkaline  to  litmus.     No 

4-30 

2.4 

albumin. 

A       A- 

8.5 

\ 

Clearer,  pale  yellow.     Acid  to  phenolphthal- 

4-4o 

ein.     Albumin  present. 

5.00 

4.0 

1 

5-15 

2.0        1 
Few  drops  Y 

Clear,    acid   to   phenolphthalein.     Albumin 
present. 

5-45 

Few  drops  | 

6.00 

3-0 

J 

Experiment  25.  —  Belgian  hare;  weight  iioo  grams.  Fed  wheat 
and  grass.  Snugly  tied  into  holder.  Urine  obtained  with  a  soft 
rubber  catheter. 


Time. 


Urine 
in  c.c. 


Remarks. 


4 

00 

1 .0       "1 

4 

15 

2.0         ^ 

Tied    down.     Alkaline,    turbid,    thick.     No 

4 

30 

Few  drops  [ 

albumin. 

4 

45 

1-5       J 

5 

00 

2.0       1 

5 
5 

15 
30 

^■5        i>    Urine  clear,  acid  to  litmus.     Albumin  present. 

2o             1 

S 

45 

3-0       J 

5 

46 

Liberated.     Returned  to  cage. 

When,  now,  rabbits  fed  the  same  food  are  treated  from 
an  experimental  standpoint  in  an  identical  way  but  have 
in  addition  a  concentrated  salt  solution  injected  intrave- 
nously, the  albuminuria  does  not  develop. 


NEPHRITIS 


139 


Experiment  26.  —  Black  rabbit;  weight  917  grams.  Fed  wheat 
and  grass.  Snugly  tied  into  animal  holder.  Urine  obtained  with 
a  soft  rubber  catheter.  105  c.c.  |  molecular  NaCl  solution^  are 
given  intravenously  in  the  course  of  the  experiment  at  the  rate  of 
5  c.c.  every  five  minutes. 


Remarks. 


Thick,  chrome  yellow,  alkaline.     No  albumin. 

Injection  begun. 
Thick,  chrome   yellow,  alkaline.     No  albumin. 
Clearer.     No  albumin. 


Time. 

Urine, 
in  c.c. 

4 

00 

7.5     1 

4 

15 

2.5 

4 

30 

7-5 

4 

45 

22. o(?)- 

5 

00 

23.0 

5 

15 

36.5    y 

5 

30 

32.0    1 

5 

45 

27.5    J 

5 

46 

—  1 

Clear  as  water.    Neutral  to  litmus.    No  albumin. 


Animal  well.     Released  and  killed  by  blow  on 
head.     Nothing  abnormal  noted  on  autopsy. 


Experiment  27.  —  Belgian  hare;  weight  919  grams.  Fed 
wheat  and  grass.  Snugly  tied  into  holder.  Urine  obtained  with  a 
soft  rubber  catheter.  105  c.c.  ^  molecular  NaCl  solution  are  injected 
intravenously  in  the  course  of  the  experiment  at  the  rate  of  5  c.c. 
every  five  minutes. 


Time. 

Urine 
in  c.c. 

Remarks. 

4.0     1 
2.5 

Alkaline  to  litmus,  thick,  yellow. 

No  albumin. 

3 

3 

^6 
30 

Injection  begun. 
Somewhat  clearer.     No  albumin. 

3 

45 

20.0 

.4 

00 

57-5 

4 
4 

15 
30 

40.0    . 
390    1 

Clear,  colorless.    Neutral  to  litmus. 

No  albumin. 

4 

45 

29.0 
37-0  J 

5.00 

As  there  is  much  reason  to  believe  that  a  mixture  of 
different  salts  when  injected  intravenously  is  less  poison- 
ous than  any  pure  salt  solution,  I  made  the  following 
experiments  with  Ringer  solution. 

*  That  is  a  2.925  per  cent  solution  of  sodium  chloride. 


I40  NEPHRITIS 

Experiment  28,  —  Belgian  hare;  weight  901  grams.  Fed  wheat 
and  grass.  Snugly  tied  into  holder.  Urine  obtained'.with  a  soft 
rubber  catheter-  In  the  course  of  the  experiment  there  are  injected 
intravenously  135  c.c.  of  a  Ringer  solution  X  4/  at  the  rate  of  5  c.c. 
every  five  minutes. 


Time. 

Urine 
in  c.c. 

Remarks. 

1.40 

4.0 

Turbid,  alkaline  to  litmus.     No  albumin. 

1-45 

2.00 

4.0 

Injection  into  ear  begun. 

Turbid,  alkaline  to  litmus.     No  albumin. 

2.15 

16.0    ^ 

2.30 
2.45 

38.0 
47-0    r 

Clear,  alkaline.     No  albumin. 

3.00 

40.5 
32.0  J 

315 

330 
3-45 

I3-0    ) 
7.0    \ 

Clear,  neutral.     No  albumin. 

4.00 

6.0    ) 

4-05 

No  urine 

Animal  well.     Returned  to  cage. 

Experiment  29.  —  Belgian  hare;  weight  823  grams.  Fed  wheat 
and  grass.  Tied  tightly  into  holder.  Urine  obtained  with  a  soft 
rubber  catheter.  In  the  course  of  the  experiment  there  are  injected 
125  c.c.  of  a  Ringer  solution  X  4,  at  the  rate  of  5  c.c.  every  five 
minutes. 


Time. 

Urine 
in  c.c. 

Remarks. 

I -50 

Tied  down. 

1-55 

Injection  into  ear  begim. 

2.10 

2.25 

30 

Turbid,  alkaline.     No  albumin. 

2.40 

18.0 

Clear,  alkaline.     No  albumin. 

2.55 

130^ 

3.10 

17.0 

3-25 

20.0  y 

Clear,  neutral  to  litmus.     No  albumin. 

3  40 

8.0 

3-55 

4-o^ 

4.00 

Dies.     Nothing  abnormal  noted  on  autopsy. 

^  The  sodium,  potassium,  calcium  chloride  mixtures  that  are  known  as 
Ringer  solutions  have  a  different  composition  with  different  authors.  I 
used  the  following:  NaCl  0.7,  CaCl2  0.0026,  KCl  0.035,  and  H2O  enough  to 
make  100  c.c.  Ringer  solution  X  4  means  four  times  this  amount  of  salts 
in  each  100  c.c,  a  solution  which  has  then  about  the  same  osmotic  concen- 
tration as  a  ^  molecular  NaCl  solution,  as  used  in  the  previous  experiments. 


NEPHRITIS 


141 


Experiment  30.  —  Belgian  hare;  weight  855  grams.  Fed  wheat 
and  grass.  Tied  tightly  into  holder.  Urine  obtained  with  a  soft 
rubber  catheter.  In  the  course  of  the  experiment  there  are  injected 
150  c.c.  o£  a  Ringer  solution  X  4,  at  the  rate  of  5  c.c.  every  five 
minutes. 


Time. 

Urine 
in  c.c. 

Remarks. 

I.O 

Turbid,  alkaline.     No  albumin.     Tied  down  and 

2    ""^ 

6^ 

intravenous  injection  into  ear  begun. 

2 

45 

1-7 

3 

00 

3-6 

3 

15 

II. 0 

12.5         > 
21.0 

Urine  clears  until  it  looks  like  water.     No  albu- 

3 
3 

30 
45 

min  at  any  time. 

4 

00 

25.0 

4 

15 

23.0       J 

4 

30 

25-o(?)1 

9.5    I 
12.5    f 

10. 0       J 

4 
5 

45 
00 

Clear,  acid.     No  albumin  at  any  time. 

5 

15 

r 

Killed.     On  autopsy  nothing  abnormal  except 

5  20 

...  j 

that  25  c.c.  fluid  are  obtained  from  the  peri- 
toneal cavity! 

Our  interest  in  these  experiments  has  thus  far  centered 
in  the  development  and  the  nondevelopment  of  an  albu- 
minuria. Let  us  now  retrace  our  steps  and  see  what 
has  happened  so  far  as  urinary  secretion  is  concerned,  for 
we  were  rather  particular  to  emphasize  the  fact  that  the 
ability  of  the  kidney  to  secrete  water  was  perhaps  the 
best  index  of  its  functional  activity.  What  we  are  inter- 
ested in  knowing  is  concerned  with  a  problem  of  immediate 
practical  worth.  Can  the  secretion  of  urine  from  a  nephritic 
kidney,  or  one  threatened  with  a  nephritis,  he  maintained  at  a 
normal  level  or  he  increased  hy  the  giving  of  various  salts? 

The  experiments  detailed  above  already  suffice  to  answer 
this  in  the  affirmative,  and  let  it  be  noted  that  this  holds 
true  even  in  the  case  of  sodium  chloride  which  in  recent 
years  has  been  particularly  warmly  criticised,  it  having  even 
been  maintained  by  not  a  few  authors  that  this  particular 


142 


NEPHRITIS 


salt  is  responsible  for  the  water  retention  in  nephritis  (and 
in  certain  other  diseases  associated  with  oedema).  That 
such  a  beUef  is  unwarranted  is  proved  as  soon  as  we  com- 
pare with  each  other  Figs.  23,  24,  and  25,  and  Experi- 
ments 22,  23,  24,  25,  26,  27,  28,  29,  and  30,  upon  which  these 
are  based.  All  the  figures  are  drawn  to  the  same  scale 
(though  they  have  not  been  reproduced  on  the  same  scale) . 
The  rate  of  urinary  secretion  is  indicated  in  number  of 
cubic  centimeters  obtained  in  each  15  minutes. 

Figure  22  shows  normal  urinary  secretion  in  three  rabbits 
that  were  loosely  tied  into  an  animal  holder.     The  curves 


0  Houi-s 


Fig.  22. 


10 

' 

8 

- 

/  \ 

6 

4 

- 

/              \ 
/        \        / 

2 
CC. 

'/^ 

^ 

0  Hours 


Fig.  23. 


a,  h,  c,  and  d  of  Fig.  23  (based  respectively  on  Experiments 
25,  22,  24,  and  23)  show,  when  compared  with  the  curves  of 
Fig.  22,  how  the  secretion  of  urine  is  diminished  when,  in- 
stead of  being  loosely  tied  into  the  animal  holder,  the  rabbits 


NEPHRITIS  143 

are  so  snugly  tied  down  as  to  embarrass  their  respiration. 
The  diminished  secretion  gives  way  to  an  enormously  height- 
ened one  if  animals  similarly  treated  are  injected  with  a  con- 
centrated sodium  chloride  solution.  Figure  24,  drawn  to  the 
same  scale  as  Fig.  23,  shows  this  very  well.  The  curve  a  is 
taken  from  Experiment  27,  curve  h  from  Experiment  26. 
These  experiments  (as  others  to  be  described  directly)  show 
very  well  that  sodium  chloride  does  not  lead  to  a  retention 
of  water  by  the  living  animal. 

Let  us  now  look  at  Fig.  25  which  shows  the  curves 
obtained  by  injecting  concentrated  Ringer  solution.  Evi- 
dently all  salts  (that  have  not  specific  poisonous  effects)  if 
injected  in  sufficient  concentrations  increase  the  output  of 
urine.  The  curves  a,  b,  and  c  are  constructed  respectively 
from  Experiments  28,  29,  and  30.  As  noted  in  the  proto- 
cols the  rabbits  were  again  snugly  tied  into  animal  holders, 
but  not  only  did  none  of  them  develop  an  albuminuria  but, 
in  consequence  of  the  injection  of  the  concentrated  Ringer 
solution,  the  urinary  output  was  enormously  increased  in  all. 

§2- 

We  will  now  consider  a  second  method  of  inducing  a 
nephritis,  namely,  through  the  injection  of  acid  into  an 
animal,  and  see  if  our  concentrated  sodium  chloride  is 
again  able  to  prevent  or  relieve  the  signs  of  a  nephritis  as 
thus  induced.  As  the  following  experiment  shows,  sodium 
chloride  when  injected  intravenously,  in  concentrated  solution, 
simultaneously  with  a  hydrochloric  acid  solution  of  a  con- 
centration which  we  found  in  Experiments  13  and  14  (pages 
38  and  39)  to  lead  to  the  symptoms  of  a  most  intense  acute 
nephritis,  practically  suppresses  this  entirely.  The  albumi- 
nuria scarcely  appears,  and  there  are  no  casts,  no  red  blood 
corpuscles,  no  hcemoglobinuria,  no  decrease  in  the  amount  of 
urinary  secretion,  and  no  general  oedema. 


144 


NEPHRITIS 


0  Hours 


Fig.  24. 


NEPHRITIS 


HS 


146 


NEPHRITIS 


Experiment  31.  —  Belgian  hare;  weight  2136  grams.  Has  been 
fed  hay,  oats,  corn,  and  greens.  In  the  course  of  the  experiment  there 
are  injected  intravenously  at  a  uniform  rate  140  c.c.  of  the  following 
mixture:  150  c.c.  xV  normal  HCl  plus  4.666  grams  sodium  chloride 
and  enough  water  to  make  the  whole  up  to  160  c.c.  This  yields  a 
final  solution  that  is  |  molecular  so  far  as  the  sodium  chloride  is  con- 
cerned.    Urine  obtained  with  a  catheter. 


Time. 

Urine 
in  c.c. 

Remarks. 

1 

Catheterized.     Weighed  and  fastened  to  animal 

3  30 

board. 

3-45 

Injection  into  ear  begun. 

1 

Slightly  turbid,  neutral  to  litmus  paper.     No  al- 

4.00 

03 

bumin.    No  casts. 

1 

Clear  as  water,  barely  reddens  blue  litmus  paper. 

4-15 

17.0 

No  albumin.     No  casts. 

61.0 

\ 

Clear,  barely  affects  blue  litmus  paper.     Faint 

4 -30 

shimmer  of  albumin!     No  casts! 

64.5 
58.0 
38.0 

r 

Urine  clear,  barely  affects  blue  litmus   paper. 

4-45 

1 
< 

Faint   trace    of    albumin.        No    casts.        No 

5-00 

haemoglobinuria  at  any  time.      No  red  blood 

5-15 

I 

corpuscles  in  the  urine. 

5.18 

I  .0 

Dies. 

Total  amount  of  urine  secreted  since  beginning  injection  239.8  c.c. 
Autopsy.  Weight  2035  grams!  Nothing  abnormal  is  noted.  The 
body  cavities  contain  no  fluid.  The  blood  seems  to  coagulate 
abnormally  rapidly. 

It  might  be  insisted  in  criticism  of  this  experiment,  that 
while  sodium  chloride  is  thus  able  to  counteract  the  effects 
of  an  acid  in  producing  a  nephritis,  it  cannot  relieve  such 
after  once  being  established.  This  criticism  is  met  in  the 
following  Experiment  32,  in  which  a  nephritis  is  first  in- 
duced by  injecting  (practically)  pure  acid,  after  which  its 
relief  is  brought  about  by  injecting  ^  molecular  sodium 
chloride. 


Experiment  32.  —  Belgian  hare;  weight  2343  grams.  Fed  hay, 
oats,  corn  and  greens.  Urine  obtained  with  a  soft  rubber  catheter. 
In  the  course  of  the  first  i  \  hours  of  the  experiment  there  are  injected 
at  a  uniform  rate  125  c.c.  of  the  following  mixture:  120  c.c.  to  normal 


NEPHRITIS 


147 


HCl  plus  8  c.c.  f  molecular  NaCl,  in  consequence  of  which  all  the 
signs  of  a  nephritis  develop.  For  the  acid  mixture  is  then  substituted 
a  pure  |  molecular  NaCl  solution  of  which,  up  to  the  end  of  the 
experiment,  there  are  injected  125  c.c.  Coincident  with  this  change 
in  the  character  of  the  injection  fluid  all  the  signs  of  the  nephritis 
are  seen  to  disappear. 


Time. 


Urine  in 
cubic  centi- 
meters. 


Remarks. 


2.45 
3.00 

3-15 
3-30 
3-45 
4.00 

4.15 
30 


50 


1-5 


0.7 


7.0     ^ 

I 

20.0      < 

42.0  j 
60.0  < 
53-0  I 
32.0  j 
ii.o(?)| 


Catheterized.  Turbid,  light  yellow,  faintly  al- 
kaline to  litmus  paper.   No  albumin.    No  casts. 

Weighed.  Tied  to  animal  holder.  Intravenous 
injection  of  acid  mixture  into  ear  begun.  Urine 
turbid,  light  yellow,  faintly  alkaline  to  litmus 
paper.     No  albumin.     No  casts. 

Urine  neutral  to  litmus  paper.  No  albumin. 
No  casts. 

Urine  neutral  to  litmus  paper.  No  albumin. 
No  casts. 

Urine  faintly  acid.  Albumin.  Isolated  casts. 
Epithelial  cells  and  red  blood  corpuscles. 

Urine  has  a  pink  tinge.  More  albumin.  Nu- 
merous casts  and  a  larger  number  of  red  blood 
corpuscles.  Injection  of  acid  mixture  stopped. 
Injection  of  \  molecular  NaCl  begun. 

Urine  decidedly  red  (haemoglobinuria).  Albu- 
min content  still  rising.  Fewer  casts  and  red 
blood  corpuscles. 

Pink  color  to  urine.  Albumin  decreasing.  No 
casts  can  be  found  after  long  search  of  sedi- 
mented  urine. 

Pale  pink.  Albumin  decreasing.  No  casts  or 
red  blood  corpuscles. 

Like  water.  Barely  visible  trace  of  albumin. 
No  casts  or  blood  corpuscles. 

Like  water  and  neutral  to  litmus  paper.  No 
albumin.  No  casts.  No  blood  cells.  Injection 
stopped,  as  animal  has  embarrassed  respiration. 

Some  urine  accidentally  lost  as  animal  dies.  No 
albumin.     No  casts.     No  blood  cells. 


Autopsy.  —  Weight  2342  grams.  Nothing  abnormal  in  any  of  the 
organs.  The  peritoneal  cavity  is  wetter  than  normal.  The  pericar- 
dial and  pleural  cavities  are  empty. 

A  number  of  interesting  facts  come  to  light  in  the  two 
experiments  just  detailed.     Let  us  first  ask  about  the  out- 


148  NEPHRITIS 

put  of  urine.  In  Fig.  26  we  find  in  the  curves  a  and  b 
(Experiments  13  and  14)  a  graphic  representation  of  the 
amount  of  urine  secreted  when  a  to  normal  hydrochloric 
acid  solution  (in  |  molecular,  that  is  0.733  P^^  cent  sodium 
chloride,  added  to  reduce  somewhat  the  haemolytic  action 
of  the  acid)  is  injected  intravenously.  When  w^e  compare 
these  curves  with  those  of  Fig.  22  (normal  secretion  in 
rabbits),  we  notice  that  in  spite  of  the  great  injection  of 
water,  the  urinary  output  lies  below  the  normal.     The 


10 

8 
6 

/    V 

6     / 

"      c 



2 
CC. 

s^,..-- 

...y 

• 

3  Hours 

1 

2 

3 

Fig.  26. 

presence  of  the  acid  along  with  the  water  brings  it  to  pass 
that  the  water  is  retained  in  the  body;  in  other  words,  an 
oedema  develops.  The  same  factor,  therefore,  which  we 
are  holding  responsible  for  certain  of  the  kidney  changes 
in  nephritis,  is  responsible  for  one  of  the  most  prominent 
symptoms  of  such  kidney  disease,  namely,  the  oedema. 

How  enormously  the  urinary  output  is  increased  if  a  con- 
centrated sodium  chloride  solution  is  injected  along  with 
the  hydrochloric  acid  is  apparent  when  Fig.  27,  drawn  to 
the  same  scale,  is  compared  with  Fig.  26.  And  when  we 
look  through  the  protocols  we  find  that  this  increased  uri- 
nary output  is  associated  with  a  loss  of  weight  by  the  animal, 
in  other  words,  a  failure  to  develop  an  oedema,  or  the  re- 
duction or  total  disappearance  of  such  as  may  be  existing. 


NEPHRITIS 


149 


ISO 


NEPHRITIS 


Clearly,  therefore,  salts,  including  sodium  chloride,  all  tend 
to  reduce  oedema,  as  I  have  previously  insisted. 

Another  point  of  interest  in  these  two  experiments  is  the 
fact  that  when  enough  sodium  chloride  is  injected  along 
with  the  acid,  the  haemoglobinuria  fails  to  develop.  As  is 
well  knowTi  a  pure  acid  solution  when  injected  intrave- 
nously leads  to  a  rapid  and  extensive  destruction  of  the  red 
blood  corpuscles  (haemolysis)  and  the  escape  of  haemoglobin 
in  the  urine.  The  only  reason  why  some  sodium  chloride 
was  given  along  with  the  acid  injections  in  the  various  ex- 
periments described  in  this  volume,  in  which  the  effects 
of  the  pure  acid  on  the  kidney  were  particularly  sought, 
was  to  escape  in  part  this  so  great  dissolution  of  the  red 
blood  corpuscles.  When  enough  sodium  chloride  is  added 
the  haemolytic  action  of  the  acid  is  avoided  altogether,  as 
Experiment  31  shows.  This  fact  is  of  interest  and  im- 
portance not  only  because  it  teaches  us  that  by  increasing 
the  salts  in  the  diet  we  can  relieve  the  signs  and  symptoms 
of  parox>^smal  haemoglobinuria,  ^  but  because  it  was  a  result 
to  be  expected  if  a  theory  of  haemolysis  which  I  have  pre- 
viously advanced^  should  be  correct. 

Incidentally,  these  last  two  experiments  in  conjunction 
with  Experiments  12,13  ^^^  ^4  (p^-ges  37  to  39)  serve  to  meet 
a  criticism  that  might  have  been  raised  against  our  experi- 
ments on  asphyxia  nephritis,  in  which  it  might  have  been  said 
that  the  great  urinary  secretion  obtained  after  injecting  salt 
solutions  was  due  merely  to  the  injection  of  so  much  water. 

§3- 
As  Max  Herrmann  first  showed,  direct  interference  with 
the  blood  supply  to  the  kidney  leads  to  very  destructive 
changes  in  this  organ  in  an  incredibly  short  space  of  time 

1  Oscar  Berghausen:  Unpublished  paper. 

2  Martin  H.  Fischer:  Kolloid  Zeitschr.  6,  146  (1909)  and  (Edema,  166, 
New  York,  1910. 


NEPHRITIS 


151 


—  the  output  of  urine  falls  or  may  be  stopped  entirely  and 
albumin,  casts,  and  blood  are  found  in  such  as  is  secreted. 
If  the  kidneys  are  examined  these  are  found  to  be  swollen, 
maybe  grayish,  and  to  present  varying  degrees  of  haemor- 
rhage into  the  kidney  substance.  The  following  experi- 
ment illustrates  this. 


Experiment  33.  —  Belgian  hare;  weight  2335  grams.  Fed  hay, 
oats,  corn,  and  greens.  Urine  obtained  with  a  catheter.  The  right 
renal  artery  and  vein,  and  the  left  renal  artery  are  clamped  for  one- 
half  hour. 


Time. 

Urine 
in  c.c. 

Remarks. 

2.05 

-1 

0.008  gram  morphine  hydrochloride  given  sub- 

cutaneously. 

C 

Clear,  brownish  yellow,  faintly  acid  to  litmus. 

2-15 

150     \ 

No  albumin.    No  casts.     After  catheterizing 
the  animal  is  weighed. 

2.50 

Tied  into  holder. 

3.00 

0.5  1 

Right  renal  artery  and  vein  and  left  renal  artery 

are  clamped. 

3.15 

3-30 

Clamps  removed. 

3-45 

4.00 

.o| 

Much  albumin.      Hyaline   casts   and  red   blood 

415 

corpuscles. 

4-30 

4-45 

0.5  \ 

0.8  ] 

Thick,  turbid,  acid  to  litmus.     Full  of  albumin 

5.00 

and  casts. 

5-15 

0.8  1 

Thick,  turbid,  acid  to  litmus.     Full  of  albumin 

5-30 

and  casts. 

5-31 

Animal  appears  well,  is  killed. 

Autopsy.  —  Kidneys  are  swollen  and  deep  red,  but  otherwise  show 
nothing  strikingly  abnormal  to  the  naked  eye. 

The  urinary  output  in  this  experiment  is  illustrated  in 
curve  c  of  Fig.  28.  Let  us  now  see  how  an  animal  similarly 
treated  fares  if  it  receives  an  intravenous  injection  of  a 
"  physiological,"  \  molecular  (0.733  per  cent)  sodium  chlo- 


152 


NEPHRITIS 


CC. 


0       Hours    1 


Fig.  28. 


NEPHRITIS 


153 


ride  solution.  Such  an  experiment  serves  to  answer  two 
very  important  questions.  First,  is  the  giving  of  water  to 
a  case  of  "  acute  nephritis  "  dangerous  because  it  "  throws 
work  on  the  kidney  "  and  we  need  to  "  protect "  this  organ 
against  doing  any  work;  and  second,  does  the  administra- 
tion of  sodium  chloride  aggravate  such  a  nephritis  because, 

Experiment  34.  —  Belgian  hare;  weight  2184  grams.  Fed  hay, 
oats,  corn,  and  greens.  Urine  obtained  with  a  catheter.  The  right 
renal  artery  and  vein,  and  the  left  renal  artery  are  clamped  for 
one-half  hour.  Thereafter,  215  c.c.  of  a  |  molecular  NaCl  solution 
are  injected  at  a  uniform  rate  intravenously. 


Time. 


11.20 
11.40 

12.10 

12.25 
12.40 

12.50 

I    05 
1 .20 

1-35 


Urine 
in  c.c. 


2.0 
4.7 

12.0 


I  50 

12.5 

2.05 

150 

2.20 

18.5 

2-35 
2.50 

30s 
3.06 

19.0 
20.0 
21 .0 

Remarks. 


0.016  gram  morphine  hydrochloride  given  sub- 

cutaneously. 
Thick,    yellow,    turbid,    acid    to    rosolic    acid. 

No   albumin.     No   casts.      Catheterized   and 

weighed. 
Same.      R.ight  renal  artery  and  vein  and  left 

renal  artery  clamped. 

Clamps  removed. 

Injection  of  \  molecular  NaCl  into  ear  begun. 

Accident  to  needle  interrupts  injection  for  10 

minutes. 
Full  of  albumin,  epithelial,  finely  granular,  and 

hyaline  casts. 
Acid  to  rosolic  acid.     Full  of  albumin,  epithelial, 

finely  granular,  and  hyaline  casts. 
Clear  as  water.     Albumin  going  down.     It  is 

noted  that  there  is  decidedly  more  albumin  in 

this  experiment  than  when  \  molecular  NaCl  is 

used,  volume  of  urine  duly  considered. 
Decided  drop  in  albumin.     Still  some  casts. 
Clear  as  water.     Albumin  present  in  traces  only. 

Occasional  cast  only. 
Same.     Trace  of  albumin  visible  after  standing. 

No  albumin.     No  casts. 

Killed. 


Autopsy.  Weight  2269  grams. 
Pleural  and  pericardial  cavities  dry. 
organ. 


6.0   c.c.    fluid  in  peritoneum. 
Nothing  abnormal  noted  in  any 


154  NEPHRITIS 

as  some  say,  it ''  further  increases  the  work  of  the  kidney  " 
or  because  it  ''  irritates  "  this  organ?  A  no  inconsiderable 
portion  of  the  therapeutic  world  to-day  insists  on  both 
restriction  of  water  and  of  sodium  chloride  in  cases  of  acute 
nephritis.  That  both  should  be  given  and  that  the  sodium 
chloride,  far  from  adding  itself  as  a  factor  of  evil  to  the 
water,  really  counteracts  the  only  bad  effects  this  might 
have  (through  favoring  the  swelling  of  the  kidney  and 
washing  out  salts)  is  shown  by  the  results  of  the  Experi- 
ment 34. 

The  increased  urinary  output,  in  consequence  of  the  in- 
jection of  the  I  molecular  sodium  chloride  solution,  is 
clearly  evident  when  curve  h  of  Fig.  28,  based  on  this 
experiment,  is  compared  with  the  curve  c  as  obtained  in 
the  previously  described  Experiment  33.  We  note,  more- 
over, that  with  the  concentration  of  sodium  chloride  em- 
ployed in  Experiment  34  a  not  inconsiderable  amount  of 
the  injected  water  is  retained,  in  other  words,  the  animal 
develops  an  oedema.  In  the  terms  of  the  osmotic  theory  of 
water  absorption  (which  we  do  not  accept)  this  would  be 
explained  by  saying  that  a  0.733  P^^  cent  sodium  chloride 
solution  has  a  lower  osmotic  concentration  than  the  body 
fluids  of  the  rabbit.  Many  clinicians  who  believe  that  so- 
dium chloride  "  leads  to  oedema  "  might  be  inclined  to  say 
that  this  experiment  supports  their  contention.  That  it 
does  not  is  shown  by  the  following  Experiment  35  in  which 
an  animal,  again  rendered  nephritic  by  clamping  the  renal 
vessels,  is  again  injected  with  the  same  amount  of  water 
at  the  same  rate,  but  the  concentration  of  the  sodium 
chloride  is  further  increased  (to  |  molecular  NaCl,  that  is 
2.918  per  cent).  As  the  protocol  and  curve  a  of  Fig.  28 
show,  the  urinary  output  under  such  circumstances  is  still 
further,  really  enormously  increased,  and  also  not  only  does 
no  oedema  develop,  but  the  animal  actually  loses  in  weight. 


NEPHRITIS 


155 


To  the  interpretation  of  these  various  findings,  which  it 
was  entirely  possible  to  predict,  we  shall  come  immediately. 

Experiment  35.  —  Black  rabbit;  weight  2778  grams.  Fed  hay, 
oats,  corn,  and  greens.  Urine  obtained  with  a  catheter.  The  right 
renal  artery  and  vein,  and  the  left  renal  artery  were  clamped  for 
one-half  hour.  Thereafter,  the  animal  received  at  a  uniform  rate 
an  intravenous  injection  of  170  c.c.  I  molecular  sodium  chloride 
solution. 


Time. 

Urine 
in  c.c. 

Remarks. 

1-55 

1 

0.016  gram  morphine  hydrochloride  are  given 

subcutaneously. 

r 

Yellow,  turbid,  alkaline  to  litmus.    No  albumin. 

2.20 

14.0 

\ 

No  casts.     After  catheterizing  the  animal  is 

I 

weighed. 

r 

Yellow,  clear,  alkaline.    No  albumin.     No  casts. 

2.45 

2-3 

< 

Right  renal  artery  and  vein,  and  left  renal  ar- 

3.00 
3-iS 

I 

tery  are  clamped. 

Clamps  removed. 

3-25 

Intravenous  injection  of  |  molecular  NaCl  begun. 

1 

Filled    with   casts    and    red    blood    corpuscles. 

3  40 

3 

i 

Fairly  sets  with  albumin. 

3-55 

32 

5 

Last  portions  clear  as  water. 

4.10 

68 

0 

1 

4-25 

73 

0 

Clear  as  water.     Acid  to  phenolphthalein,  alka- 

4.40 

59 

0 

line  to  rosolic  acid.    Faintest  trace  of  albumin 

4-55 

46 

5 

r 

only.     No   casts.    Occasional  red  blood   cor- 

5-IO 

2,7 

0 

puscles. 

5-25 

39 

5 

\\ 

Animal  killed.     Approximately  10  c.c.  urine  lost 

5-26 

? 

\ 

in   interval    between   stopping   injection  and 
making  autopsy. 

Autopsy. — Weight  2554  grams!  19.0  c.c.  fluid  found  in  perito- 
neal cavity.  Pleural  and  pericardial  cavities  are  dry.  Kidneys  are 
slightly  grayish. 

The  following  Experiment  36  shows  for  what  a  long 
period  the  blood  supply  to  the  kidney  may  be  cut  off  and 
yet  the  dangers  ordinarily  incident  to  such  a  procedure 
(partial  to  complete  suppression  of  urine)  be  reduced  by 
giving  a  concentrated  salt  solution.  The  experiment  was 
really  undertaken  to  indicate  how  the  so-feared  conse- 


156 


NEPHRITIS 


quences  of  temporary  occlusion  of  the  blood  vessels  in  oper- 
ations on  the  kidney  may  be  largely  avoided  —  a  discussion 
to  which  we  shall  return  immediately. 

ExPERQiENT  36.  —  White  and  blue  rabbit;  weight  2344  grams. 
Fed  hay,  oats,  corn,  and  greens.  Urine  obtained  with  a  catheter. 
The  right  renal  artery  and  vein  and  the  left  renal  artery  and  vein  are 
clamped  for  i\  hours.  After  an  interval,  90  c.c.  ^  molecular  NaCl 
solution  are  injected  at  a  uniform  rate  intravenously. 


Time. 

Urine 
in  c.c. 

Remarks. 

9.20 

1 

0.016  gram  morphine  hydrochloride  are  given 

subcutaneously. 

9  50 

Tied  down. 

10.05 

1-3 

Deep  brownish-yellow.  No  albumin.  No  casts. 
Renal  blood  vessels  are  clamped. 

10.20 

10.35 

10.50 

11.05 

11.20 

11-35 

Clamps  removed. 

11.50 

12.05 

12.20 

12.35 

12.50 

I -05 

1.20 

1-35 
1-55 

Injection  of  |  molecular  NaCl  into  ear  begun. 

2. 10 

2.25 

0.3 

' 

2.40 

0.4 

Filled   with   albumin   and  hyaline  casts  (exclu- 

2.55 

0.4 

sively). 

3.10 

0.8 

..' 

Injection  stopped. 

3  25 

2.6 

1 

Urine  clearer.  Filled  with  hyaline  and  granular 
casts. 

3 -40 

2.8 

Casts  fewer. 

3-55 

i-S 

No  casts. 

3-55to 
5-25 

^.3 

i 

No  casts.  Red  blood  corpuscles  found  (trau- 
matic). 

5  40 

1-5 

No  casts. 

541 

Killed. 

Autopsy.  — Weight  2300  grams.  10  c.c.  fluid  in  peritoneal  cavity. 
1,2  c.c.  in  right  pleural  cavity.  Left  unusually  moist.  Kidneys  soft 
and  somewhat  gray. 


NEPHRITIS 

The  secretion  of  urine  in  this  experi- 
ment is  represented  graphically  in  Fig. 
29.  The  first  arrow  indicates  the  point 
in  the  experiment  when  the  clamps  were 
removed.  Up  to  point  of  the  second 
arrow  no  urine  was  obtained.  At  this 
time  the  sodium  chloride  injection  was 
started.  The  secretion  of  urine  began 
less  than  half  an  hour  afterwards. 

§  4- 

It  behooves  us  now  to  pause  for  a 
moment  and  to  study  the  just  described 
experiments  in  order  to  discover  the 
principles  that  underlie  the  results  ob- 
tained, for  only  by  knowing  these  can 
we  hope  to  put  them  to  any  intelligent 
therapeutic  use.  In  the  light  of  the 
ideas  developed  in  this  volume,  and  my 
remarks  on  urinary  secretion^  the  follow- 
ing seems  to  me  safe  ground. 

The  living  organism  represents  in  the 
resting  state  a  series  of  colloids  which 
are  saturated  with  water.  The  blood 
and  lymph  constitute  an  integral  part  of 
this  system.  No  water  can  be  absorbed 
by  the  living  organism,  and  none  be 
given  off  except  as  conditions  are  first 
offered  in  the  body  as  a  whole  or  locally 
(individual  organs  or  cells),  which  in- 
crease or  decrease  this  normal  relation- 

1  Martin  H.  Fischer:  (Edema,  180.  New  York, 
1910.  See  also  Kolloidchemische  Beiheftc,  2,  304 
(1911). 


157 


158  NEPHRITIS 

ship  between  the  colloids  and  the  water  bound  to  them.  As 
in  our  discussion  of  the  kidney  we  are  dealing  with  the  prob- 
lem of  secretion,  we  can  at  once  recall  to  mind  experimental 
and  clinical  evidence  to  support  such  a  view  by  remember- 
ing that  in  absolute  starvation  urinary  secretion  ceases  (prac- 
tically) entirely.  And  so  we  are  not  surprised  to  find  that 
the  urinary  output  of  a  normal  rabbit  shortly  after  we  stop 
feeding  it  shows  signs  of  diminution  and  soon  thereafter  signs 
of  complete  cessation  (Fig.  22).  From  this  we  can  immedi- 
ately learn  a  practical  point  that  is  ignored  medically  all 
too  often,  and  that  is  that  the  only  way  to  increase  the  uri- 
nary output  is  to  give  water,  and  (if  we  ignore  the  skin  and 
respiration)  we  can  say  that  we  increase  this  in  proportion 
to  the  amount  of  water  given.  Many  if  not  all  of  the  diu- 
retics act  in  the  same  way.  They  are  diuretics  only  because 
they  make  for  conditions  in  the  body  which  decrease  the  avidity 
with  which  the  colloids  of  the  body  are  holding  on  to  their  water. 
Let  us  see  now  what  happens  when  we  tie  our  otherwise 
normal  rabbit  so  snugly  into  an  animal  holder  that  we  in- 
terfere with  its  easy  respiration.  That  the  urinary  output 
falls  under  such  circumstances  is  shown  in  Fig.  23.  What 
happens  here  is  this:  we  favor  under  these  circumstances 
the  accumulation  of  carbon  dioxide  and  other  acids  in  his 
body.  This  raises  the  avidity  with  which  the  colloids  of 
all  the  tissues  of  the  body  hold  on  to  their  water,  and  so 
none  is  left  over  to  be  secreted  as  urine.  The  animal  is,  in 
other  words,  at  once  put  into  a  condition  similar  to  that 
attained  after  several  hours  by  the  animal  simply  kept  off 
of  food  and  water.  In  addition  to  any  local  acid  effect  we 
may  have  in  the  kidney  (swelling  of  the  kidney,  etc.),  we 
have  also  in  this  case  an  acid  effect  upon  all  the  tissues 
of  the  body.  Not  only  therefore  is  the  kidney  placed  in 
a  position  in  which  it  cannot  secrete  as  well  as  normally, 
but  the  material  necessary  for  this  secretion  (water)  is  also 


NEPHRITIS  159 

withheld.  Parenthetically  we  may  add  that  a  state  similar 
to  that  induced  here  by  tying  the  animal  down  is  obtained 
when  we  give  a  dose  of  morphine,  cocaine,  atropine,  arsenic, 
an  anaesthetic  like  chloroform  or  ether,  an  excessi-ve  dose  of 
alcohol,  or  a  nitrite. 

Essentially  the  same  state  of  affairs  is  produced  if  we 
inject  an  acid  solution  intravenously.  The  acid  acts  upon 
the  tissue  colloids,  increases  their  affinity  for  water,  and 
these  therefore  absorb  and  hold  on  to  all  that  is  given  them 
in  these  experiments  along  with  the  acid.  And  so  we  have 
again  none  left  over  to  be  secreted  by  the  kidney.  The 
animal  retains  the  water,  increases  in  weight;  it  develops 
an  "  oedema."  This  general  effect  of  the  acid  on  the  body 
as  a  whole,  adds  itself  therefore  to  the  acid  changes  that 
occur  in  the  kidney  itself  under  such  circumstances.  The 
acid  circulating  in  the  kidney  makes  the  cells  here  swell. 
This  compresses  the  blood  vessels  of  the  kidney,  and  so  the 
state  of  the  kidney  becomes  still  more  precarious.  To  its 
already  serious  acid  state  the  kidney  adds  further  danger 
by  reducing  its  own  blood  supply  (which  means  a  further 
formation  and  accumulation  of  acid  in  the  kidney),  and  so 
a  vicious  circle  is  estabhshed. 

Let  us  consider,  first  of  all,  what  must  happen  if  we  give 
pure  water  to  such  an  animal.  Its  effects  are  in  part  good, 
in  part  bad.  Very  evidently  only  by  giving  water  can  we 
hope  to  get  the  body  colloids  generally  once  more  saturated 
with  water  and  so  get  some  left  over  for  a  urinary  secretion, 
and  only  as  we  get  a  urinary  secretion  can  we  hope  to  wash 
out  the  acids  (and  other  toxic  substances)  that  are  killing 
the  kidney  cells.  And  this  holds,  as  we  shall  see,  even 
when  we  deal  with  a  case  of  generalized  oedema.  The  only 
bad  effects  of  giving  water  reside  in  favoring  the  swelling 
of  the  kidney.  But  this  feature  we  can  avoid,  as  we  have 
said  before,  by  giving  salts. 


i6o  NEPHRITIS 

To  the  relief  of  all  the  conditions  that  characterize  our 
picture  of  nephritis  comes  the  administration  of  salt  (along 
with  the  water).  The  salts  —  including  sodium  chloride  — 
reduce  the  amount  of  water  that  can  be  held  by  the  body 
colloids  generally,  and  so  this  freed  water  now  becomes 
available  for  urine.  The  kidney  itself  shares  in  this  process 
and  by  shrinking  admits  a  better  circulation  to  be  once 
more  estabhshed  through  it.  In  this  way  ever\'thing  tends 
to  be  reestabhshed  in  a  normal  way  once  more.  The 
body  now  loses  water,  and  so  the  animal  weight,  in  other 
words  the  oedema  disappears  again.  Under  the  same  cir- 
cumstances the  kidney  proteins  become  less  soluble  and 
so  the  albuminuria  goes.  The  disappearance  of  the  casts 
is  pecuHarly  interesting.  Immediately  follo\^dng  a  salt  in- 
jection the  number  of  casts  seems  increased.  We  note, 
moreover,  that  they  are  smaller,  and  while  hyaline  casts 
may  have  predominated  before,  granular  ones  now  nil  the 
field.  The  sudden  apparent  increase  in  the  number  of 
casts  is  due  to  the  shrinkage  under  the  influence  of  the  in- 
creased salt  concentration  of  the  casts  as  they  lie  in  the 
kidney  tubules,  and  so  their  easier  and  sudden  washing  out 
from  these  tubules  by  the  increased  urinary  flow  obtained 
under  the  same  circumstances.  The  granular  casts  repre- 
sent the  reconversions  of  the  hyaline  casts  back  into  the 
granular  under  the  influence  of  the  salt. 

§  5- 
We  come  now  to  the  highly  important  matter  of  apply- 
ing what  has  been  found  to  hold  in  animals  to  human  cases. 
The  credit  of  having  been  the  first  to  adapt  the  principles 
outhned  in  this  volume  to  chnical  cases  belongs  to  James  J. 
Hogan.  An  abstract  of  his  first  two  cases  follows.  Since 
then  others  of  my  friends  and  colleagues  have  used  alkalies, 
salts,  and  water  for  the  relief  particularly  of  the  acuter  ne- 


NEPHRITIS  i6i 

phri tides,  and  with  favorable  results.  My  thanks  are  due 
all  these  for  permitting  me  to  use  the  facts  that  are  con- 
tained in  the  following  brief  outlines  of  their  cases. 

The  entire  purpose  of  our  therapy  must  be  to  get  alkali 
into  our  patient  in  order  to  neutralize  the  acids  present; 
to  get  salt  into  him  to  aid  in  the  reduction  of  the  oedema 
of  the  kidney  (and  other  organs) ;  and  finally,  to  give  him 
water  in  large  doses  at  regular  intervals  in  order  to  have 
''free"  water  available  for  urine.  How  we  may  accom- 
phsh  our  ends  by  administering  these  by  mouth,  or  in  the 
acuter  cases  by  giving  properly  concentrated  solutions  of 
sodium  carbonate  and  sodium  chloride  by  rectum  or  in- 
travenously is  indicated  in  the  abstracts. 

Case  i. —  {Dr.  James  /.  Hogan,  Vallejo,  California.)  Mrs. 
R.,  pregnant  and  practically  at  term,  entered  the  hospital 
March  7,  at  5.30  p.m.,  complaining  of  continuous  uterine 
pain.  The  patient  had  a  general  oedema.  Signs  and  symp- 
toms indicating  that  a  nephritis  had  existed  for  at  least 
some  days  past  were  evident,  but  no  proper  examination 
of  the  urine  had  been  made.  The  os  on  examination  was 
found  rigid.  Because  of  the  intense  pain  0.015  gram  mor- 
phine was  given  h}^odemiically  at  9.00  p.m.  She  went  to 
sleep  but  awoke  at  11.00  in  a  severe  convulsion.  The 
patient  w^as  catheterized  and  60  c.c.  of  bloody  urine  of  a 
s>Tupy  consistency  were  obtained.  On  testing  this  for  albu- 
min it  fairly  set.  Casts,  cellular  detritus,  red  blood  cells, 
etc.,  were  found  microscopically.  600  c.c.  of  an  0.85  per 
cent  sodium  chloride  solution  were  given  by  rectum  and 
immediate  emptying  of  the  uterus  was  deemed  necessary. 
This  was  done  under  ether  anaesthesia  and  as  the  os  was 
very  rigid  required  a  half  hour.  A  second  convulsion  oc- 
curred on  the  operating  table.  Immediately  after  the  oper- 
ation another  500  c.c.  of  an  0.85  per  cent  sodium  chloride 
solution  were  given  by  rectum.  Between  this  time  (11.30 
P.M.,  March  7)  and  4.50  p.m.,  March  11,  in  other  words,  for 
practically  four  days,  no  urine  could  be  obtained  by  cath- 
eter.    During  this"^  time  no  con\nalsions  occurred  and  the 


1 62  NEPHRITIS 

patient's  mind  remained  clear.  A  continuous  salt  drip  was 
used  in  the  rectum  and  water  and  magnesium  sulphate  were 
given  by  mouth,  but  no  evidence  of  a  return  of  urinary 
function  was  obtainable.  It  was  now  decided  to  use  a 
more  concentrated  sodium  chloride  solution  and  alkali. 
The  following  mixture  was  therefore  prepared. 

Sodium  carbonate  (crystallized)  ^  .     .       20  grams 

Sodium  chloride 14  grams 

Water  enough  to  make 1000  c.c. 

This  was  injected  into  the  rectum  at  body  temperature 
by  a  continuous  drip  method.  In  an  hour  and  ten  min- 
utes 30  c.c.  of  bloody  urine  were  obtained,  and  an  hour 
later  80  c.c.  more.  From  now  on  the  urine  fairly  streamed 
out.  The  secretion  continued  and  the  albumin  and  casts 
entirely  disappeared  from  the  urine  by  the  fourth  day. 
The  patient  made  an  uninterrupted  recovery. 

Case  2. —  {Dr.  James  J.  Hogan,  Vallejo,  California.)  Mrs. 
W.,  22  years  old.  Dr.  Hogan  was  called  in  consultation  on 
the  evening  of  March  11,  and  found  the  patient  uncon- 
scious with  practically  complete  suppression  of  the  urine 
that  had  lasted  for  twenty-four  hours.  The  unconscious- 
ness had  lasted  for  twelve  hours.  The  nephritis  in  this 
case  was  secondary  to  scarlet  fever.  The  formula  used  in 
Case  I  was  given  by  the  continuous  drip  method  per  rectum. 
The  urinary  flow  recommenced  after  four  hours ;  on  the  fol- 
lowing day  her  mind  had  cleared,  and  the  patient  made  a 
subsequent  uneventful  recovery. 

Case  3.  —  {Dr.  H.  Kennon  Dunham,  Cincinnati.) 
Master  M.,  7  years  old,  was  seen  on  April  30,  191 1,  by 
Dr.  Wm.  C.  Schmidter  in  a  rather  mild  attack  of  scarlet 
fever.  The  temperature  at  no  time  ran  above  101°  F.  In 
spite  of  the  apparent  mildness  of  the  attack,  the  child  devel- 
oped urinary  symptoms.     On  May  7,  when  Dr.  Dunham 

1  When  the  crystallized  sodium  carbonate  is  not  at  hand,  and  only  the 
ordinary  dried  preparation  is  available,  only  about  one  third  of  this  must  he 
employed,  for  approximately  two  thirds  of  the  crystalUzed  substance  is 
water  of  crystallization. 


NEPHRITIS  163 

was  first  summoned  in  consultation,  a  complete  suppres- 
sion of  urine  had  lasted  for  fifty-one  hours,  the  child  was 
conscious,  but  very  stupid,  presenting  a  grave  picture  of 
intoxication.  The  eyehds  and  ankles  were  swollen,  the 
pulse  105,  respiration  24. 

At  4.00  A.M.  the  following  mixture  was  prepared  and  its 
injection  into  the  rectum  begun: 

Sodium  chloride 30  grams 

Sodium  carbonate  (crystallized)      ...     20  grams 
Water 1000  c.c. 

The  injection  required  one  and  a  half  hours.  About 
180  c.c.  were  rejected,  the  remainder  of  the  above  solu- 
tion was  retained.  Three  and  a  half  hours  after  the  in- 
jection was  completed  the  patient  passed  involuntarily  a 
large  watery  stool.  Ten  hours  after  the  completion  of  the 
injection  he  passed  a  small  amount  of  highly  colored  urine. 
Following  this  at  short  intervals  came  large  voidings  of 
urine  which  were  lost  into  the  bed  as  the  child  could  not 
control  himself  sufficiently  to  use  a  bedpan.  Not  until 
this  secretion  had  lasted  for  four  hours  could  the  urine  be 
collected.  Not  counting  that  which  was  lost  there  were 
collected  2272  c.c.  of  urine  in  the  first  twenty-four  hours 
after  urinary  secretion  commenced.  The  first  specimens  of 
urine  obtained  were  so  filled  with  albumin  as  to  set  into  a 
solid  mass  on  boiling.  The  amount  of  albumin  rapidly  de- 
creased in  amount,  so  that  during  the  second  day  after  the 
injection  only  a  moderate  reaction  for  albumin  was  obtained, 
and  on  the  ninth  day  it  disappeared  entirely.  The  intense 
stupor  left  the  child  within  the  first  twenty-four  hours 
after  injection,  and  on  the  third  day  he  was  actively  inter- 
ested in  his  surroundings  and  free  from  oedema.  His 
urinary  secretion  after  being  started  was  readily  main- 
tained by  the  milk  diet  on  which  he  had  been  from  the 
first  and  to  which  alkaline  mineral  water  was  added  ad 
libitum. 

Case  4.  —  {Dr.  Lemuel  P.  Adams,  Oakland,  California.) 
Mrs.  E.,  26  years  old  and  a  primipara,  began  to  feel  below 
par,  became  pale,  and  developed  a  generalized  oedema  when 


1 64  NEPHRITIS 

pregnant  seven  and  a  half  months.  The  secretion  of 
urine  was  low,  and  this  contained  much  albumin  and  various 
casts.  Her  condition  gradually  grew  worse,  so  that  it  was 
deemed  wise  to  put  her  to  bed  in  the  hospital.  For  ten 
days,  here  on  a  milk  diet,  and  cared  for  in  the  approved 
ways,  she  showed  no  improvement,  passing  between  240 
and  360  c.c.  of  urine  per  twenty-four  hours,  filled  with 
albumin,  casts,  and  red  and  white  blood  corpuscles.  As 
she  now  began  to  develop  twitchings,  was  extremely  oedema- 
tous  and  nearly  blind,  and  as  the  onset  of  convulsions  was 
feared,  premature  labor  (at  8  months)  was  induced  through 
gradual  dilatation  of  the  uterine  os  by  means  of  water  bags. 
Complete  suppression  of  urine  followed  dehvery.  After 
this  had  lasted  for  thirty-one  hours  and  no  urine  had  come 
consequent  upon  hot  packs,  cupping,  digitalis,  etc.,  a  slow  in- 
jection of  the  following  mixture  into  the  rectum  was  begun : 

Sodium  chloride 14  grams 

Sodium  carbonate  (crystallized)      ...     20  grams 
Water 1000  c.c. 

Urine  began  to  come  four  hours  after  the  injection  was 
commenced  and  amounted  to  1536  c.c.  in  the  first  twenty- 
four  hours.  Two  injections  daily  of  500  c.c.  each  of  the 
above  formula  were  continued  for  three  days,  together  with 
water,  milk,  and  cereals  by  mouth.  On  the  second  day 
2176  c.c.  of  urine  were  obtained,  on  the  third  2140,  on  the 
fourth  2180,  and  on  the  fifth  1856.  On  the  fifth  day  casts 
and  blood  cells  had  entirely  disappeared  from  the  urine 
and  only  the  faintest  trace  of  albumin  remained.  The 
oedema  had  diminished  greatly,  eyesight  was  returning, 
and  the  patient  was  actively  interested  in  her  surroundings. 
On  the  following  day  the  last  of  the  albumin  was  gone  and 
the  patient  went  on  to  an  uneventful  recovery. 

Case  5.  —  {Drs.  Otto  P.  Geier  and  J.  L.  Tuechter,  Cin- 
cinnati.) G.  L.,  a  34-year-old  attorney,  developed  a 
severe  tonsilHtis  involving  both  tonsils  on  May  17,  191 1. 
His  temperature  was  103.5°  F.,  pulse  120.  The  urine  was 
very  scanty,  high  colored,  and  contained  albumin  and  casts. 
The  next  day  the  patient  had  intense  headache,  and  in  the 


NEPHRITIS  165 

evening  became  delirious.  During  these  second  twenty- 
four  hours  of  his  illness  he  passed  but  90  c.c.  of  urine,  very 
smoky  in  color  and  filled  with  albumin,  red  and  white  cor- 
puscles and  casts  of  all  sorts.  On  the  third  day  of  his  illness 
he  passed  no  urine  at  all.  His  dehrium  continued  and  his 
temperature  remained  at  103°  F.,  his  pulse  at  124.  Late 
at  night  he  was  given  the  following  mixture  per  rectum: 

Sodium  chloride 14  grams 

Sodium  carbonate  (crystallized).     .     .     20  grams 
Water 1000  c.c. 

In  his  delirium  most  of  this  first  injection  was  rejected. 
At  3.00  A.M.,  May  20,  the  injection  was  therefore  repeated. 
About. 500  c.c.  of  the  formula  were  retained.  At  6.00  a.m. 
150  c.c.  of  dark,  thick  urine  were  obtained,  which  on  heat- 
ing fairly  set  into  a  jelly.  The  urinary  secretion  became 
more  profuse  as  the  day  wore  on,  and  in  the  first  twenty- 
four  hours  after  the  successful  injection  1184  c.c.  of  urine 
were  obtained.  As  the  urinary  secretion  increased,  the 
drowsy  delirium  passed  away,  the  headache  disappeared, 
and  the  patient  volunteered  that  he  felt  well.  The  tem- 
perature fell  to  101°  F.,  the  pulse  rate  to  100.  The  later 
specimens  of  urine  voided  in  these  twenty-four  hours  after 
the  successful  injection  were  clear  and  amber  in  color  and 
contained  only  a  little  albumin,  and  few  casts  and  blood 
cells.  The  rectal  injections  of  500  c.c.  of  the  above  formula 
were  repeated  May  21  (temperature  99.5°  F.,  pulse  90)  and 
May  22  (temperature  normal,  pulse  70),  and  the  patient 
was  urged  to  take  as  much  Vichy  water  by  mouth  as  he 
could.  The  urine  secreted  May  21  measured  1376  c.c, 
that  secreted  May  22,  1408  c.c.  Some  albumin  and  casts 
were  found  in  the  former,  only  a  trace  together  with  some 
red  blood  corpuscles  but  no  casts  in  the  latter.  On  May  23 
all  urinary  signs  had  disappeared,  and  the  patient  made  an 
uneventful  recovery. 

Case  6.  —  {Dr.  Dudley  Smith,  Oakland,  Cahfornia.) 
Mrs.  W.,  aged  30,  and  seven  months  pregnant,  presented 
herself  for  examination  in  May,  191 1,  with  a  history  of 
nephritis  and  threatened  eclampsia  in  her  first  pregnancy, 


1 66  NEPHRITIS 

ten  years  before.  The  second  pregnancy  three  years  be- 
fore had  been  uneventful.  Urinary  examination  when  the 
patient  first  presented  herself  was  negative.  On  June  7, 
she  began  to  show  albumin  in  her  urine  and  marked  signs 
of  general  intoxication.  (Edema  of  the  face  and  feet  de- 
veloped. She  was  put  to  bed  and  placed  on  a  milk  diet, 
and  salhie  cathartics  were  administered.  Under  this  treat- 
ment she  got  no  better.  About  the  first  of  July,  active 
administration  of  alkalies  was  begun  in  the  form  of  one  to 
one  and  a  half  grams  of  sodium  carbonate  dissolved  in  a 
glass  of  plain  water,  or  Vichy  water,  every  two  hours. 
Marked  and  positive  improvement  occurred  in  all  her 
general  symptoms  and  the  oedema  disappeared  entirely. 
She  was  permitted  to  get  out  of  bed  again,  but  the  alkali 
therapy  was  continued.  On  this  regime  she  was  carried  to 
full  term  with  no  further  general  symptoms  of  consequence. 
Her  urinary  output  lay  between  1800  and  2800  c.c.  daily 
and  some  albumin  and  casts  continued  in  the  urine.  On 
July  24  she  complained  of  severe  continuous  uterine  pain, 
and  with  this  came  a  marked  reduction  in  the  urinary  out- 
put, extreme  nervousness,  and  severe  headache  with  nausea 
and  vomiting.  On  the  morning  of  July  25  the  urinary  secre- 
tion had  stopped  entirely.  She  was  sent  to  the  hospital 
at  noon  and  the  following  formula  was  slowly  injected  into 
the  rectum: 

Sodium  chloride 14  grams 

Sodium  carbonate  (crystallized)     .     .     15  grams 
Water 1000  c.c. 

At  3.00  P.M.  the  uterine  pain,  the  headache,  and  the  nau- 
sea had  disappeared  and  the  patient  went  to  sleep.  At  4.00 
P.M.  the  rectal  infusion  was  given  a  second  time  and  almost 
a  liter  was  absorbed.  At  11.00  p.m.,  258  c.c.  of  urine 
were  voided  and  the  patient  passed  a  good  night,  sleeping 
soundly.  The  following  morning  500  c.c.  of  urine,  very 
high  in  albumin,  casts,  and  blood  were  passed.  At  three 
o'clock  of  this  day,  she  again  developed  severe  headache, 
nausea,  and  vomiting,  and  was  unable  to  retain  the  rectal 
infusions  or  anything  by  mouth.  At  10.00  p.m.  all  the 
symptoms  had  so  increased  in  severity,  that  300  c.c.  of  the 


NEPHRITIS  167 

above  solution  were  given  intravenously.  In  fifteen  min- 
utes the  patient  volunteered  the  information  that  her  head- 
ache and  nausea  were  gone.  She  was  comfortable  until  the 
next  afternoon  when  periodic  uterine  pains  developed,  and 
the  headache  and  vomiting  returned.  The  patient  was 
taken  to  the  operating  room,  and  the  cervix  was  dilated 
slowly  by  hand.  Delivery  of  the  hving  child  was  ac- 
complished in  an  hour  and  a  half.  This  was  followed  by 
another  intravenous  injection  of  645  c.c.  of  a  solution 
containing  7I  grams  crystallized  sodium  carbonate  and 
14  grams  sodium  chloride  to  the  liter.  In  the  following 
twenty-four  hours  2200  c.c.  of  urine  were  voided,  and  as 
the  nausea,  vomiting,  etc.,  had  disappeared  it  was  an  easy 
matter  to  maintain  such  a  urinary  output  by  giving  water 
and  alkalies  by  mouth.  Albumin  and  casts  disappeared 
from  the  urine  on  the  fourth  day  and  the  patient  had  an 
uneventful  convalescence. 

Case  7.  —  (Dr.  W.  A.  Clark,  San  Leandro,  California.) 
Mrs.  C.  H.,  aged  35,  and  pregnant  for  the  second  time, 
presented  herself  for  examination  in  March,  191 1.  She 
had  menstruated  slightly,  and  for  the  last  time,  January  22. 
A  year  previously  she  had  given  birth  to  a  healthy  child 
at  term,  though  in  the  later  months  of  her  pregnancy  her 
limbs  and  face  had  swelled,  she  had  much  headache,  and 
her  eyes  had  troubled  her.  At  the  time  of  her  first  visit, 
and  repeatedly  afterward,  physical  examination  and  ex- 
amination of  the  urine  showed  nothing  abnormal.  On 
August  II,  she  showed  a  well-marked  generalized  oedema, 
and  complained  of  headache,  extreme  restlessness,  sleep- 
lessness, dimness  of  vision,  and  constant  nausea.  Her  uri- 
nary secretion  had  fallen  to  500  c.c.  per  twenty-four  hours, 
was  highly  acid,  and  high  in  albumin  and  casts.  She  was 
immediately  sent  to  the  hospital  and  kept  in  bed  on  a  diet 
rich  in  water,  alkalies,  vegetables,  and  milk.  Epsom  salts 
were  administered  by  mouth,  and  0.85  per  cent^  sodium 
chloride  solution  was  repeatedly  injected  slowly  into  the 
rectum.  On  this  regime  all  of  her  symptoms  and  signs  in- 
cluding the  albumin  and  casts  disappeared,  and  the  urinary 
output  rose  so  that  2200  to  2674  c.c.  were  voided  every 


i68  NEPHRITIS 

twenty-four  hours.  August  26  the  patient  felt  so  well  that 
she  insisted  on  getting  out  of  bed  and  busied  herself  about 
her  room.  On  the  second  day  following  this  renewed 
activity,  her  headaches  again  showed  themselves,  and  her 
nervousness  and  sleeplessness  returned.  On  August  29  her 
nausea  and  vomiting  became  severe,  and  her  vision  very 
dim.  The  oedema  of  the  legs  and  face  returned,  and  her 
urinary  output  fell  sHghtly,  to  1984  c.c.  WQien  the  heat 
test  w^as  applied  to  the  urine,  the  w^hole  became  solid. 
This  condition  continued  until  11.30  p.m.  of  August  30, 
when  the  headache,  nausea,  vomiting,  etc.,  were  so  severe 
that  it  was  decided  to  give  alkali  and  salt  intravenously. 
The  following  formula  was  given: 

Sodium  carbonate  (crystallized)      .     .     10  grams 

Sodium  chloride 14  grams 

Water 1000  c.c. 

In  an  hour  the  patient  volunteered  the  information  that 
her  headache  and  nausea  were  better,  and  that  she  felt 
brighter.  She  slept  well,  and  passed  the  next  morning 
comfortably.  Examination  of  the  urine  passed  in  the 
night  and  early  morning  showed  a  decided  drop  in  the 
amount  of  albumin  excreted.  Even  though  the  subjective 
S}TTiptoms  of  the  patient  continued  well,  the  albumxin  con- 
tent of  the  urine  again  rose  so  that  on  the  morning  of 
September  i  this  was  sufficient  to  make  the  contents  of 
the  test  tube  again  set  in  a  soKd  mass  when  boiled.  The 
amount  of  urine  obtained  continued  good,  being  1984  and 
2048  c.c.  respectively,  for  the  last  two  twenty-four-hour 
periods.  It  was  deemed  best  to  empty  the  uterus,  and  at 
10.00  A.M.  of  September  i,  dilatation  of  the  uterine  os  by 
means  of  rubber  bags  was  begun.  Rhythmic  pains  began 
two  hours  later  and  as  these  increased  in  number  and 
severity,  the  patient's  headache  and  nausea  increased, 
and  the  urinary  secretion  fell.  At  4.00  p.m.  the  patient 
vomited  and  developed  a  twitching  of  the  face  and  arms. 
This  continued  at  intervals  until  11.00  p.m.  when  two  liters 
of  the  alkali-salt  mixture  of  the  composition  previously 
used  in  this  case  were  injected  intravenously.  Shortly 
after  this,  the  subjective  symptoms  of  the  patient  became 


NEPHRITIS  169 

better,  and  she  fell  asleep,  passing  a  fairly  good  night,  and 
examination  of  the  urine  again  showed  a  decided  drop  in 
the  amount  of  albumin  present.  The  general  condition  of 
the  patient  continued  good,  and  on  the  evening  of  Sep- 
tember 2,  she  was  delivered  under  chloroform  anaesthesia 
of  a  1750-gram,  living,  female  child  (left  shoulder  pre- 
sentation with  version).  On  the  operating  table  the 
patient  received  1000  c.c.  of  0.85  per  cent  sodium  chloride 
solution  under  the  skin,  and  for  subsequent  treatment  the 
patient  was  given  this  same  salt  solution  by  rectum  and 
alkahne  water  (a  gram  of  sodium  carbonate  in  a  glass  of 
water  every  hour)  by  mouth.  The  urinary  secretion  on 
this  regime  never  fell  below  2200  c.c.  On  September  4 
the  albumin  in  the  urhie  had  dwindled  to  a  trace,  and  on 
the  next  day  it  had  disappeared  entirely.  Examination 
of  the  urine  twice  daily  from  this  time  on  invariably  showed 
an  alkaline  reaction  to  litmus  paper  and  no  albumin.  The 
general  oedema  disappeared  on  the  third  day  after  delivery. 
On  September  17  the  patient  was  fully  convalescent. 

Case  8.  —  {Dr.  N.  A,  Hamilton,  FrankHn,  Ohio.)  Mrs. 
C,  27  years  old,  and  a  primipara  in  the  seventh  month, 
showed  nothing  abnormal  on  examination,  September  8. 
On  September  20  some  albumin  was  found  in  the  urine, 
and  on  September  27  it  was  present  in  abundance.  Her 
general  condition  was  good. 

At  10.00  P.M.,  October  2,  she  was  seized  with  sudden 
nausea  and  vomiting  which  continued  through  the  night. 
At  3.30  A.M.,  October  3,  she  had  short  lapses  of  conscious- 
ness. Headache  was  severe;  there  was  some  oedema  of  the 
face  and  legs;  the  pulse  was  100  and  hard.  Veratrum  was 
given  by  hypodermic  injection.  At  8.30  a.m.  her  pulse  had 
fallen  to  52;  her  temperature  was  normal.  No  urine  had 
been  passed  through  the  night,  but  at  this  time  she  passed 
30  c.c.  The  patient  was  dizzy,  still  vomiting,  had  pain  in 
her  neck,  and  her  sight  was  blurred.  She  w^as  now  given 
800  c.c.  of  a  strong  (hypertonic)  sodium  chloride  solution 
(1.5  per  cent)  by  rectum.  This  was  all  retained.  At  11.30 
a.m.  90  c.c.  of  dark-colored  urine  filled  with  casts  and  con- 
taining so  much  albumin  that  on  boiling  it  fairly  set  was 


lyo  NEPHRITIS 

passed.  Another  800  c.c.  of  the  sodium  chloride  solution 
were  now  given  and  at  2.00  p.m.  an  unknown  amount  of 
urine  was  lost  with  a  stool.  Twenty  minutes  later  a  con- 
\ailsion  lasting  a  minute  occurred,  and  this  was  repeated  a 
half  hour  later.  The  patient  was  vomiting,  and  could  not 
distinguish  colors.  There  was  a  general  twitching  of  the 
muscles.  A  general  anaesthetic  was  given  at  3.30  and  an 
attempt  made  to  dilate  the  very  rigid  uterine  os  instru- 
men tally.  At  5.00  p.m.  the  membranes  ruptured,  and  at 
the  same  time  30  c.c.  of  dark  brown  urine  were  obtained 
by  catheter.  At  6.00  p.m.  the  temperature  of  the  patient 
was  100.2°  F.  by  axilla.  Another  injection  of  800  c.c.  of 
the  strong  saline  solution  was  given  by  rectum  at  this  time 
and  repeated  at  8.00  p.m.  but  neither  was  retained  well. 
At  10.00  p.m.  a  little  urine  (estimated  as  30  c.c.)  was  passed 
with  a  stool.  At  midnight  the  patient's  temperature  was 
100.2°  F.,  she  was  dizzy,  could  not  distinguish  between'men 
and  women,  and  was  unable  to  differentiate  white  from 
black.  At  this  time  she  was  given  the  following  formula 
intravenously : 

Sodium  carbonate  (crystallized)     .     .     20  grams 

Sodium  chloride 28  grams 

Water 2000  c.c. 

The  injection  required  an  hour.  While  giving  the  in- 
jection the  patient  volunteered  the  information  that  her 
nausea  had  left  her,  and  that  her  headache  was  disappear- 
ing. At  2.30  A.M.,  October  4,  she  passed  75  c.c.  of  dark 
brown  urine  filled  with  casts  and  fairly  solid  with  albumin 
on  boiling.  At  4.00  a.m.  she  passed  another  75  c.c.  and  at 
6.45  A.M.  95  c.c.  During  these  hours  she  slept  at  inter- 
vals. When  she  awakened  her  headache  and  nausea  were 
gone,  and  she  could  distinguish  between  gross  objects,  and 
recognize  colors.  From  now  on  and  through  the  day  she 
was  plied  with  water  by  mouth  and  five  injections  of  400 
c.c.  each  of  the  above  sodium  carbonate-sodium  chloride 
mixture  were  given  by  rectum.  These  were  well  retained. 
Urine  was  voided  about  every  three  hours,  and  in  increas- 
ing quantity.  By  midnight,  that  is  to  say  in  the  first 
twenty-four  hours  after  the  intravenous  injection,  she  had 


NEPHRITIS 


171 


voided  572  c.c.  not  counting  two  ''large"  voidings  that 
were  lost.  The  later  portions  of  this  urine  were  clearer  in 
color  and  contained  much  less  albumin  than  the  specimens 
already  described. 

In  the  night  of  October  5,  the  patient  went  into  labor, 
and  at  8.00  a.m.  forceps  were  introduced  and  she  was  de- 
livered of  a  macerated  foetus.  In  spite  of  the  exertions  of 
labor  she  passed  320  c.c.  urine,  between  midnight  and  the 
time  of  the  delivery  of  the  placenta.  Through  the  night 
the  alkali-salt  enemas  could  not  be  retained,  but  through 
the  day  she  took  and  retained  four  enemas  of  400  c.c.  each. 
In  this  second  period  of  twenty-four  hours  she  passed  734 
c.c.  of  urine.  After  delivery,  her  temperature,  which  on 
the  night  before  had  risen  to  103.6°  F.  (by  mouth),  fell  to 
normal. 

In  the  twenty-four  hours  of  October  6,  she  received  and 
retained  four  enemas  of  500  c.c.  each  of  the  alkali-salt 
mixture,  and  drank  freely  of  water  (a  glass  every  hour). 
She  passed  in  this  period  1840  c.c.  of  urine,  not  counting 
two  voidings  that  were  lost  with  the  stools.  The  later  por- 
tions of  this  urine  contained  only  a  little  albumin.  The 
patient  was  sleeping  well,  and  relishing  her  toast,  gruel, 
eggs,  milk,  and  broth. 

In  the  next  two  days  the  alkali-salt  enemas  were  re- 
duced to  two  daily,  one  night  and  morning,  and  then 
stopped  entirely.  She  was  given  a  liberal  diet,  and  water 
was  insistently  given  by  mouth.  Lemonade  and  orange- 
ade were  urged.  When  the  alkali  was  no  longer  given  by 
rectum,  sodium  carbonate  (0.5  gram)  was  given  in  a  glass 
of  water  as  often  as  the  patient  would  take  it  both  day 
and  night,  and  she  was  asked  to  salt  her  food  hberally. 
Her  urinary  output  on  this  regime  was  as  follows: 


October  7 . 
October  8. 
October  9 . 
October  10 
October  11 
October  12 
October  13 


3616      c.c.  October  14.  .24ooH- c.c. 

3264      c.c.  October  15.  .4096+ c.c. 

3520     c.c.  October  16.  .3808     c.c. 

2528      c.c.  October  17.  .3200     c.c. 

2108     c.c.  October  18.  .1920     c.c. 

2396-f  c.c.  October  19 . .  1915     c.c. 
2432 -f  c.c. 


172  NEPHRITIS 

The  great  rise  in  urinary  output  on  October  15  followed 
an  increase  in  the  amount  of  alkali  and  salt  given  by 
mouth;  the  fall  on  October  18  a  reduction  of  this. 

The  oedema  had  disappeared  and  the  albumin  dwindled 
to  a  trace  by  October  7.  This  trace  persisted  up  to  October 
19.  The  patient  developed  a  slight  temperature  (100.8°  F.) 
on  the  fourth  day  after  delivery,  but  following  intrauterine 
douches  with  bichloride  of  mercury  and  iodine  this  fell  so 
that  only  a  temperature  of  99.0°  or  99.2°  was  registered  in 
the  afternoons  up  to  October  17.  From  October  16  she 
was  given  an  unrestricted  diet,  and  on  October  17  she  sat 
up  for  the  first  time.  On  October  24  she  "is  downstairs, 
voiding  an  abundance  of  urine  and  happy." 

Case  9.  —  {Dr.  E.  A.  Majors,  Oakland,  California.) 
Mrs.  A.  B.,  pregnant  for  the  second  time  and  at  term  was 
found  in  labor  and  delivered  of  a  healthy  living  child,  in 
an  entirely  normal  way  at  i.oo  a.m.  No  previous  history 
was  obtainable.  Following  labor  she  fell  into  a  deep 
sleep  and  at  5.00  a.m.  it  was  impossible  to  arouse  her.  As 
there  was  no  evidence  of  urinary  secretion,  she  was  cathe- 
terized  at  6.00  a.m.  No  urine  was  obtained.  At  7.00  a.m. 
she  had  two  severe  convulsions.  Following  this  she  lay  in 
a  deep  stupor  with  rapid  breathing.  At  10.00  she  was 
again  catheterized  but  no  urine  was  obtained.  She  now 
received  by  slow  injection  into  the  rectum  the  following: 

Sodium  carbonate  (crystallized)    .     .         15  grams 

Sodium  chloride 14  grams 

Water 1000  c.c. 

Sixty  c.c.  of  urine  were  obtained  an  hour  after  the 
beginning  of  the  injection,  and  half  an  hour  later  another 
130  c.c.  filled  with  albumin  and  casts  were  obtained.  At 
the  same  time  the  patient  began  to  clear  mentally.  Three 
hours  after  beginning  the  injection  she  would  respond  to 
questions.  She  was  plied  with  water  by  mouth.  Later  in 
the  afternoon  500  c.c.  of  the  above  formula  were  again 
given  by  rectum  and  this  was  repeated  next  day.  In  the 
first  twenty-four  hours  1525  c.c.  of  urine  were  obtained, 


NEPHRITIS  173 

and  2240  c.c.  in  the  second.  At  the  same  time  the  albu- 
min and  casts  diminished  and  on  the  third  day  the  urine 
cleared  entirely.     Uneventful  convalescence  followed.-^ 

Case  10.  —  {Dr.  William  E.  Kiely,  Cincinnati.)  Three 
weeks  before  entering  the  hospital  S.  C.  W.,  38  years  old, 
and  a  moderate  beer  drinker,  became  short  of  breath, 
suffered  from  headaches,  and  noticed  a  swelling  of  his  legs 
and  abdomen.  Physical  examination  showed  no  disease  of 
the  heart  or  lungs,  but  fluid  in  the  pleural  and  peritoneal 
cavities,  with  a  general  oedema  of  the  subcutaneous  tissues. 
The  urine  was  low  in  amount,  of  high  specific  gravity,  and 
contained  much  albumin,  some  blood  cells,  and  hyaline 
casts.  On  this  a  diagnosis  of  (chronic)  parenchymatous  ne- 
phritis was  made.  After  twenty-five  days  of  rest  in  bed,  a 
milk  diet,  a  daily  hot  bath,  saline  cathartics,  and  digitalis, 
no  improvement  in  his  general  condition  was  noted.  There 
was  now  added  to  his  diet  a  liter  of  water  daily  containing 
25  grams  of  sodium  chloride.  Improvement  in  his  general 
signs  and  symptoms  began  immediately,  the  urinary  out- 
put rose,  the  blood  disappeared,  and  the  casts  and  albumin 
progressively  diminished  in  amount.  After  ten  days  of  this 
treatment  he  had  improved  most  markedly,  and  at  the  end 

1  The  methods  of  treatment  as  applied  in  this  volume  to  nephritis  can 
naturally  be  used  in  a  whole  series  of  clinical  conditions  in  which  a  gen- 
eralized or  localized  oedema  as  an  expression  of  a  generalized  or  a  localized 
abnormal  production  or  accumulation  of  acid  is  responsible  for  the  signs 
or  symptoms  observed.  A  detailed  discussion  of  this  problem  is  out  of 
order  here,  but  it  may  not  be  out  of  place  to  catalogue  some  of  the  con- 
ditions in  which  excellent  results  have  been  obtained.  Administration  of 
water,  alkali,  and  salt  by  mouth,  by  rectum,  or  intravenously,  works  ex- 
cellently in  the  brain  oedemas  following  injury,  arsenic  injections,  etc.; 
in  glaucoma;  in  the  oedemas  of  heart  disease;  in  the  labored  breathing  of 
arteriosclerosis;  in  the  delirium,  twitchings,  and  convulsions  seen  in  the 
acute  infectious  diseases;  in  the  marasmus  of  infants  and  children;  in 
bronchial  asthma.  C.  C.  Fihe  has  obtained  excellent  results  by  using 
salt,  alkali,  and  water  in  hay  fever  and  mucous  colitis.  In  the  latter 
condition  W .  S.  Kuder  has  also  reported  good  results.  James  J.  Hogan 
uses  salt  and  alkali  injections  with  excellent  effect  in  the  pernicious 
vomiting  of  pregnancy  even  when  no  signs  of  nephritis  or  a  generalized 
cedema  are  present. 


174 


NEPHRITIS 


of  twenty-five  days  all  signs  of  his  oedema  and  the  effusions 
into  his  serous  cavities  had  disappeared.  At  his  own  request 
he  got  out  of  bed  and  began  to  work  about  the  ward, 
and  shortly  thereafter  left  the  hospital  free  of  all  signs 
and  s}Tnptoms,  except  for  the  faintest  trace  of  albumin 
in  his  urine.  In  this  state  he  has  continued  up  to  the 
present  time  (that  is,  for  two  months  since  leaving  the 
hospital). 

Case  ii.  —  {Dr.  Julius  H.  Eichberg,  Cincinnati.)  A.  B., 
a  40-year-old  lawyer,  entered  the  hospital  in  April,  191 1, 
with  a  history  of  kidney  disease  of  eight  years'  standing. 
At  various  times  during  these  years  he  had  had  a  diagnosis 
of  chronic  parenchymatous  nephritis  made  upon  him.  He 
had  no  enlargement  of  the  heart  and  no  increased  blood 
pressure.  The  original  cause  of  the  nephritis  could  not  be 
made  out.  When  first  seen  the  patient  was  passing  about 
400  c.c.  of  urine  per  twenty-four  hours,  containing  4  grams 
of  albumin  per  liter  and  filled  with  all  varieties  of  casts. 
On  a  milk  and  vegetable  diet,  sweat  baths,  and  saline 
cathartics  his  urinary  secretion  increased  somewhat,  but 
his  general  condition  did  not  improve,  the  number  of 
grams  of  albumin  lost  each  twenty-four  hours  did  not 
decrease,  and  his  oedema,  ascites,  etc.,  increased.  After 
two  weeks  in  the  hospital  he  had  a  well-marked  oedema 
of  his  legs,  back,  chest- wall,  scalp,  and  face.  The  fluid  in 
his  abdomen  extended  to  the  umbilicus  when  sitting  up. 
While  his  general  hospital  regime  and  diet  were  kept  as 
before,  he  now  had  added  to  his  drinking  water  and  con- 
sumed each  twenty-four  hours  7  grams  of  dried  sodium  car- 
bonate. After  ten  days  of  the  carbonate  administration 
his  oedema  and  ascites  disappeared  completely,  his  urine 
increased  to  approximately  800  c.c.  per  twenty-four  hours, 
though  the  quantity  of  albumin  lost  per  twenty-four  hours 
did  not  change  perceptibly. 

The  patient  at  this  point  refused  to  continue  taking  the 
carbonate.  In  five  days  his  weight  went  up  2^  kilos.  Dr. 
Eichberg  persuaded  the  patient  to  resume  the  carbonate, 
and  at  the  end  of  another  seven  days  his  original  weight 
had  again  been  attained,  and  the  visible  signs  of  oedema 


NEPHRITIS  175 

which  had  developed  when  the  carbonate  was  discontinued 
had  once  more  disappeared.  The  urinary  output  amounted 
at  this  time  to  800  c.c.  daily,  and  the  albumin  dropped  to 
2.5  grams  per  liter. 

At  this  point  the  patient  refused  a  second  time  to  take 
the  sodium  carbonate,  and  again  the  sweUing  of  his  legs 
and  back  developed,  while  his  weight  rose  as  before,  2| 
kilos  in  less  than  a  week.  Following  this  period  he  re- 
turned a  third  time  to  the  carbonate,  and  in  six  days  had 
again  lost  his  2J  kilos  and  the  obvious  signs  of  an  oedema. 
This  is  his  state  at  the  present  writing  when  for  four  months 
he  has  been  passing  1280  c.c.  or  more  of  urine  daily,  con- 
taining some  casts  and  0.75  gram  of  albumin  per  Hter.  He 
has  left  the  hospital  in  fair  condition,  has  a  good  appetite, 
sleeps  well,  and  has  resumed  the  practice  of  his  profession. 

The  following  case  will  serve  to  illustrate  how  the  oppor- 
tunities of  relieving  the  acute  manifestations  of  nephritis 
are  decreased  pari  passu  with  the  decrease  in  the  absolute 
amount  of  kidney  substance  present. 

Case  12.  —  {Drs.  Jo.  Hamilton,  Fruitvale,  and  W.  S. 
Kuder,  Oakland,  Cahfornia.)  A.  D.  P.,  a  16-year-old  high- 
school  boy,  first  showed  albumin  and  casts  in  his  urine  three 
years  ago.  During  the  past  year,  no  analysis  of  his  urine 
had  been  made.  The  boy's  general  health  had  been  good. 
On  September  4  he  had  been  very  active,  and  that  night  he 
slept  badly.  At  six  in  the  morning  of  September  5,  he  was 
found  unconscious  and  in  a  convulsion.  The  convulsions 
were  general,  very  severe,  and  practically  continuous. 
Between  the  more  severe  paroxysms  there  was  a  constant 
twitching  of  the  body  and  extremities.  No  urine  had  been 
voided,  and  none  was  found  in  the  bladder  when  brought 
into  the  hospital  at  i.oo  p.m.  and  catheterized.  Two 
Uters  of  the  following  formula  were  at  once  injected  in- 
travenously : 

Sodium  carbonate  (crystallized).     .     .     10  grams 

Sodium  chloride 14  grams 

Water 1000  c.c. 


176  NEPHRITIS 

At  2.30  P.M.,  64  c.c.  of  highly  albuminous  urine  contain- 
ing large  numbers  of  granular  and  hyaline  casts  were 
obtained  by  catheter.  Half  an  hour  later  a  good  amount 
of  urine  was  voided  into  the  bed.  The  patient  seemed  de- 
cidedly more  relaxed  and  the  convulsions  gave  way  to  less 
severe  twitchings  in  the  legs,  arms,  and  trunk.  The  pulse 
which  pre\'iously  could  not  be  counted  dropped  to  no  and 
the  panting  respiration  fell  to  24.  At  5.00  p.m.  256  c.c. 
of  urine  were  obtained  by  catheter.  At  this  time  the  pa- 
tient was  perspiring  profusely.  At  6.00  p.m.  two  convul- 
sions of  moderate  severity  occurred.  Permission  to  give 
another  intravenous  injection  was  denied,  and  so  400  c.c.  of 
the  formula  given  above  were  injected  into  the  rectum. 
No  more  convulsions  occurred  at  this  time  and  the  twitch- 
ing stopped  entirely.  At  8.40  p.m.  96  c.c.  of  urine  were 
obtained.  At  11.00  p.m.  permission  to  give  another  two 
liters,  intravenously,  of  the  sodium  carbonate-sodium  chlo- 
ride-water mixture  was  obtained,  and  this  was  done. 
By  1. 00  a.m.  352  c.c.  of  urine  were  collected  by  catheter, 
and  at  2.00  a.m.  192  c.c.  At  3.00  a.m.  the  patient  had 
a  slight  convulsion,  and  at  4.00  he  had  a  severe  one  and 
died. 

A  hasty  physical  examination  of  this  boy  immediately 
after  being  brought  into  the  hospital  showed  no  signs  of 
oedema  anywhere,  readily  palpable  arteries  everywhere,  and 
an  enlargement  of  the  area  of  heart  dullness  toward  the  left 
and  downwards,  with  no  heart  murmurs.  On  these  find- 
ings a  diagnosis  of  chronic  interstitial  nephritis  secondary 
to  an  arteriosclerosis  was  made,  and  an  unfavorable  prog- 
nosis was  given.  It  was  felt  (on  the  theory  that  uraemia 
represents  an  oedema  of  the  brain)  that  the  convulsions 
could  be  ameliorated,  and  that  the  secretion  of  urine 
could  again  be  started,  but  more  than  this  could  not  be 
promised  as  the  degree  of  kidney  atrophy,  upon  which  the 
question  of  the  ultimate  recovery  of  the  patient  depended, 
could  only  be  guessed  at. 

An  autopsy  made  a  few  hours  after  death  confirmed 
the  clinical  diagnosis  of  generalized  arteriosclerosis  with 
hypertrophy  of  the  heart.  The  kidneys  together  weighed 
112  grams,  the  surfaces  were  rough;  the  capsule  was  inti- 


NEPHRITIS  177 

mately  adherent  to  the  kidney  parench3rma.  On  section 
the  kidneys  were  a  mottled  gray,  and  so  hard  that  they 
could  not  be  broken  by  pinching  with  the  finger  nails. 
The  cortex  was  reduced  to  a  mere  line. 

The  results  outlined  in  the  cases  that  have  been  briefly 
abstracted  here  seem  to  indicate  very  clearly  that  we  have, 
in  the  administration  of  alkalies,  sodium  chloride,  and 
water,  a  means  by  which  we  can  rapidly  combat  those 
kidney  symptoms  that  we  are  particularly  liable  to  en- 
counter in  eclampsia,  the  acute  toxic  nephritides,  the  acute 
suppressions  of  urine  that  follow  anaesthetics,  surgical  oper- 
ations of  various  sorts,  including  those  on  the  kidney  in 
which  the  blood  supply  to  this  organ  has  been  temporarily 
occluded,  alcoholic  debauches,  too  enthusiastic  use  of  the 
nitrites,  1  etc. 

While  for  the  most  part  the  alkali-salt-water  mixtures 
were  in  these  cases  given  by  slow  injection  into  the  rectum, 
there  is  no  danger,  if  a  case  is  deemed  sufficiently  acute, 
in  giving  the  mixture  intravenously.  To  do  this  the  elabo- 
rate surgical  procedures  usually  adopted  to  make  an  in- 
travenous injection  (excepting  the  asepsis)  can  be  largely 
dispensed  with.  In  the  way  of  apparatus  we  need  only  to 
insert  an  ordinary  hypodermic  needle  into  the  rubber  tube 

^  I  have  several  times  seen  alarming  falls  in  the  urinary  output  and  once 
a  complete  suppression  of  urine  with  death  of  the  patient  eight  days  later 
after  the  administration  of  nitrites  to  reduce  blood  pressure  in  cases  of 
arteriosclerosis  in  association  with  chronic  interstitial  nephritis.  As  I 
have  pointed  out,  mere  reduction  of  blood  pressure  (except  in  cases  of  haem- 
orrhage) is  scarcely  to  be  looked  upon  as  a  therapeutic  gain.  Suppression 
of  urine  is  bound  to  follow  the  lack  of  blood  supply  to  kidneys  which  are 
barely  getting  enough  with  a  high  blood  pressure.  There  is  no  justification 
for  giving  nitrites  in  chronic  interstitial  nephritis,  imless  we  can  show 
that  while  reducing  general  blood  pressure  we  are  not  at  the  same  time 
reducing  the  blood  supply  to  the  kidney  down  to  a  dangerous  point.  If  an 
arteriosclerosis  is  killing  a  kidney,  we  can  hope  to  help  the  situation  only  by 
treating  the  arteriosclerosis. 


178  NEPHRITIS 

coming  from  the  irrigation  vessel  which  is  filled  with  the 
solution  to  be  injected.  The  irrigation  vessel  is  raised  to  a 
proper  height  and,  after  all  air  has  been  driven  out  of  the 
outflow  tube,  the  h}^odermic  needle  may  be  inserted 
through  the  skin  or,  after  a  small  cut  has  been  made  into 
this,  directly  into  one  of  the  numerous  veins  in  the  forearm 
or  at  the  bend  of  the  elbow.  It  is  best  to  simply  hold  the 
needle  in  position,  but  if  so  desired  it  may  be  fastened  down 
with  an  adhesive  strap.  The  solution  must  be  injected  slowly 
so  as  to  allow  ample  time  for  mixing  with  the  blood. 

In  the  preparation  of  the  solutions  for  intravenous  injec- 
tion it  must  be  remembered  that  a  carbonate  cannot  be  boiled 
without  driving  of  its  CO2  and  so  converting  it  into  the  more 
alkaline  hydroxide.  To  get  a  sterile  solution  the  sodium  car- 
bonate is  dissolved  in  as  little  cold  distilled  and  sterilized 
water  as  possible.  The  sodium  chloride  is  then  dissolved  in 
an  appropriate  amount  of  distilled  water  and  sterilized  by 
heat.  After  this  solution  has  cooled  sufficiently  the  carbonate 
solution  is  added  to  it.  When  dried  sodium  carbonate  is  used 
instead  of  the  crystallized  only  one-third  as  much  is  to  be 
employed,  for  crystallized  sodium  carbonate  is  approximately 
two-thirds  water  of  crystallization,  j.7  grams  dried  sodium 
carbonate  is  equal  to  10  grams  of  the  crystallized. 

Some  surgeons  have  advised  and  operated  on  acutely 
nephritic  kidneys  and  stripped  the  capsule.  In  at  least 
some  instances  good  has  followed  such  a  procedure,  but 
this  can  be  expected  only  if  the  deciding  element  between 
the  recovery  of  the  affected  kidney  and  death  is  thought 
to  be  measurable  in  the  increased  circulation  obtainable 
through  the  kidney  by  stripping  the  capsule.  Even  after 
the  answer  to  this  is  given  in  the  affirmative,  then  before 
operating,  the  effects  of  an  anaesthetic  and  the  shock  of  an 
operation  must  be  considered,  and  not  unless  these  are 
taken  to  be  negligible  should  the  operation  be  done,  es- 


NEPHRITIS 


179 


pecially  since  it  appears  from  the  experiments  and  clinical 
reports  detailed  in  these  pages  that  all  that  can  be  gained 
through  an  operation  can  be  gotten  by  the  simpler  means 
of  injecting  the  proper  alkali-salt-water  solutions. 

These  alkaH-salt-water  injections  must  also  prove  of  ser- 
vice in  surgical  operations  on  the  kidney,  in  which  it  is  at 
times  deemed  necessary  to  occlude  temporarily  the  blood 
supply  to  the  kidney.  The  consequences  of  such  a  pro- 
cedure are  those  of  the  experiments  already  detailed  in 
which  the  blood  vessels  to  the  kidney  were  clamped.  It 
has  been  shown  by  C.  C.  Guthrie  ^  that  perfusion  with  a  phy- 
siological salt  solution  or  a  Ringer  solution  ^  of  kidneys  so 
treated  affects  them  more  deleteriously  than  if  they  are 
left  alone.  This  is  because  such  salt  solutions  are  not 
sufficiently  concentrated  to  prevent  the  swelling,  etc.,  of 
the  kidney  cells.  Most  perfusion  mixtures  lack  moreover 
the  necessary  colloids  —  the  water  in  them  is  free,  which 
is  not  the  case  in  blood  and  lymph. ^ 

It  is  self-evident  that  that  which  will  relieve  a  nephritis 
when  once  established  should,  when  properly  used,  prevent 
such  a  nephritis  from  developing,  and  so  we  must  consider 
how  useful  in  the  prophylaxis  of  nephritis  must  be  the 
giving  of  water,  alkalies,  and  salts.  Especially  serviceable 
must  these  prove  themselves  when  preparing  for  an  opera- 
tion, in  a  threatened  nephritis  during  pregnancy,  when  we 
deal  with  the  acute  infectious  diseases,  etc.  There  exist  as 
a  matter  of  fact  any  number  of  clinical  facts  to  prove  this. 
The  milk  diet  has,  not  without  reason,  enjoyed  for  decades 
the  popularity  that  it  has  attained.  By  giving  milk  we 
give  a  patient  a  very  useful  balanced  ration  of  fat,  carbohy- 
drate, and  protein.  But  we  do  more  than  this  —  we  give 
water  and  salts.     The  water  helps  to  wash  out  poisons  and 

1  C  C.  GiUkrie:  Arch.  Int.  Med.  5,  232  (1910). 

2  See  page  193. 


i8o  NEPHRITIS 

the  salts  contained  in  the  milk  have  a  concentration  which 
just  sufi&ces  to  do  away  with  the  effects  of  giving  an  equal 
amount  of  water  pure. 

Similar  reasoning  explains  the  beneficent  effects  of  giv- 
ing "  physiological "  salt  solution  in  large  amounts  by  rec- 
tum, intravenously  or  subcutaneously,  in  various  acute  in- 
fections. It  is  again  the  combined  effects  of  much  water  to 
wash  out  poisons  and  enough  salt  to  counteract  that  acci- 
dentally lost  ^  by  the  same  procedure  that  washes  out  the 
poison.  When  in  spite  of  such  procedures  the  signs  of  a 
nephritis  develop  we  need  to  press  alkalies  (alkaline  drinks) 
and  to  give  more  salt. 

We  will  conclude  this  section  by  giving  a  concrete  illus- 
tration of  the  fact  that,  by  increasing  the  alkali-salt  content 
of  the  body,  the  opportunities  for  the  development  of  the 
signs  of  a  nephritis  are  greatly  reduced.  For  such  a  test 
the  albuminuria  that  develops  in  athletes  after  hard  work 
was  used,  and  with  the  following  results: 

In  Experiment  19  on  page  45  we  detailed  the  quantita- 
tive findings  regarding  the  excretion  of  albumin  during  an 
ordinary  match  basket-ball  game,  as  determined  by  collect- 
ing the  urine  over  the  period  of  an  hour  and  a  half,  in 
which  time  the  game  was  played.  In  the  following  two 
experiments  the  urine  was  similarly  collected,  every  pre- 
caution being  taken  to  have  the  conditions  for  collection, 
regarding  time,  etc.,  as  nearly  the  same  as  in  the  control 
experiment.  The  athletes  were  under  no  restrictions  re- 
garding diet,  the  only  difference  being  that  in  the  two  ex- 
periments now  to  be  detailed,  the  players  took  in  addition 

1  We  have  become  all  too  inclined  to  consider  everything  that  comes  out 
in  the  urine  as  something  that  the  intelligence  of  the  kidney  has  found 
harmful  to  the  body.  It  is  scarcely  as  wise  as  this.  It  is  rather  hard  to  see, 
for  example,  why  in  a  salt-starved  animal  that  is  being  given  water,  the  ani- 
mal continues  to  eliminate  some  salt  in  the  urine  up  to  the  moment  of  death, 
when  it  is  this  very  elimination  that  is  killing  the  animal. 


NEPHRITIS  181 

to  their  ordinary  food  the  juice  of  six  sweet  oranges  in  the 
first,  and  twelve  in  the  second.  The  six  oranges  were  con- 
sumed in  the  course  of  three  hours  preceding  the  game;  the 
twelve  in  the  twelve  hours  preceding  the  game.  Oranges 
were  chosen  not  alone  because  they  are  palatable,  and  so 
offer  no  difficulty  in  having  the  men  take  them,  but  be- 
cause the  salts  contained  in  them  have  not  only  a  decided 
capacity  of  combining  with  stronger  acids,  but  the  citrates, 
malates,  etc.,  are  the  very  salts  which  act  most  powerfully 
in  reducing  the  solution  of  proteins  in  acids  (as  well  as  the 
swelling  of  organs  under  these  circumstances,  etc.).  The 
game  played  in  Experiment  37  was  decidedly  harder  than 
that  detailed  for  control  purposes  in  Experiment  19,  that 
of  Experiment  38  fully  as  hard.  The  first  five  players 
were  the  same  in  all  these  three  games,  though  the  order 
in  which  they  are  numbered  is  not  the  same. 


l82 


NEPHRITIS 


Experiment  37.  —  Juice  of  six  oranges  fed  the  players.  Urine 
collected  for  period  of  i|  hours,  during  which  time  the  play  occurred. 
Phosphotungstic-hydrochloric  acid-alcohol  reagent  used  mth&Eshach 
albuminometer. 

Before  the  Game. 


Player. 

Urine,  in  cubic 
centimeters. 

Nitric  acid  test. 

Heat  test. 

I 
2 

3 
4 
5 

232 
72 
30 
85 

280 

>        Negative         -^ 

Negative 

After  the  Game. 


Urine,  in 

Albumin 

Player. 

cubic  centi- 
meters. 

HNO3  test. 

Heat  test. 

Esbach  reading. 

excreted, 
in  grams. 

I 

62 

>| 

r 

1-25 

.078 

2 

17 

1-5 

•  025 

3 

152 

y 

Positive 

Positive  < 

0.75 

.114 

4 

42 

0.75 

.132 

5 

228 

^ 

- 

less  than  0.2 

.046 

Av.  .079 

Experiment  38.  —  Juice  of  twelve  oranges  fed  each  of  the  players. 
Urine  collected  for  period  of  i|  hours,  during  which  time  the  play 
occurred.  Phosphotungstic-hydrochloric  acid-alcohol  reagent  used 
in  Esbach  albuminometer. 


Before  the  Game. 


Player. 

Urine,  in  cubic 
centimeters. 

Nitric  acid  test. 

Heat  test. 

I 
2 

3 
4 
5 
6 

73 

170 

187 

6 

62 

>        Negative 

Negative 

NEPHRITIS 

183 

After  the  Game 

• 

Player. 

Urine,  in 
cubic  centi- 
meters. 

HNOatest. 

Heat  test. 

Esbach  reading. 

Total  albumin 

excreted,  in 

grams. 

I 

97 

1 

Positive   -l 

0.7S 

•073 

2 
3 

56 
II 

^  Positive 

1 

1-25 
1.6 

.070 
.018 

4 

44 

J 

I 

1-3 

•057 

Av.  .054 

5 
6 

44 
45 

1    Positive 

Positive    \ 

0.6 
0.2s 

.028 
.011 

Player  number  5  played  first  half  only;  number  6,  second  half  only. 

Even  when  we  count  out  the  player  in  the  control  game 
who  started  with  an  albuminuria,  and  those  in  the  succeed- 
ing games  who  did  not  play  through,  we  still  find  that  the 
albumin  secretion,  both  so  Jar  as  average  concentration  and 
average  absolute  amount  is  concerned,  is  decidedly  lower  after 
feeding  citrus  fruit  than  without  such  feeding. 

4.   On  the  Treatment  of  (Edema. 

A  generalized  oedema  constitutes  so  prominent  a  feature 
of  certain  cases  of  nephritis  that  it  of  itself  becomes  at 
times  an  object  of  treatment.  Of  the  various  methods 
that  have  been  suggested  for  the  control  of  this  condition 
we  will  take  up  only  one  for  discussion  here,  that  of  the 
question  of  salt  restriction. 

When  we  discussed  in  the  earlier  sections  of  this  paper 
the  enlargement  of  the  kidney  in  the  parenchymatous  types 
of  nephritis,  we  noted  that  this  enlargement  of  the  organ, 
which  is  in  essence  an  oedema,  can  be  reduced  through  the 
presence  of  salts,  and  as,  for  reasons  already  set  forth,  such 
oedematous  swelling  (just  what  occurs  in  the  acute  forms  of 
nephritis)  is  a  serious  menace  to  the  kidney,  because  it 
tends  to  shut  off  its  blood  supply,  it  was  recommended  to 
combat  this  condition  by  increasing  the  salt  concentration 


1 84  NEPHRITIS 

in  the  nephritic  individual.  The  thought,  of  course,  at  once 
suggests  itself  that  this  scheme  of  treatment  might  be  ex- 
tended to  the  treatment  of  the  general  oedema  occurring  in 
nephritis.^    While  such  a  course  has  for  decades  been  ap- 

1  F.  G.  Goodridge  and  William  I.  Gies  [Proc.  Soc.  Exp.  Biol,  and  Med.  8, 
io6  (191 1)],  while  apparently  accepting  the  teaching  that  the  colloids  of 
the  tissues  are  responsible  for  the  amount  of  water  held  by  them,  have  taken 
exception  to  my  assertion  that  an  abnormal  production  or  accumulation  of 
acid  in  the  tissues  of  the  body  plays  an  important  if  not  the  chief  role  in 
the  production  of  oedema,  in  that  these  increase  the  power  of  certain  of  the 
tissue  colloids  to  absorb  water.  While  it  would  not  at  all  surprise  me  to 
have  it  shown  that  some  other  or  some  series  of  other  changes  in  the  body 
tissues  than  an  abnormal  production  or  accumulation  of  acid  is  responsible 
for  the  increased  hydration  of  the  colloids  here,  which  is  the  characteristic 
feature  of  oedema,  the  experiments  of  Goodridge  and  Gies  do  not  do  this. 
These  authors  base  their  criticism  on  the  fact  that  fibrin  threads  sus- 
pended in  such  colloidal  solutions  as  gelatine,  peptone  solution,  egg  white, 
blood,  milk,  and  meat  juice,  do  not  swell  visibly  on  the  addition  of  acid  to 
these  solutions  until  this  is  added  up  to  the  point  where  it  is  "  free  "  in  the 
solution.  When  these  authors  add  acid  to  the  colloidal  solutions  in  which 
they  immerse  their  fibrin  threads  they  increase  the  hydration  by  this  means, 
not  of  the  fibrin  threads,  but  of  the  colloidal  solution  (they  give  this  the 
"oedema"),  as  they  would  find  if  they  measured  its  viscosity.  Up  to  a 
certain  point  (maximum  hydration  under  the  influence  of  the  acid)  the  ad- 
dition of  the  acid  would  therefore  tend  to  prevent  the  fibrin  from  absorbing 
water.  Only  if  acid  got  into  it  and  free  water  were  available  could  we 
expect  the  fibrin  thread  to  swell. 

The  question  has  also  been  asked  if  the  views  expressed  in  this  book  and 
in  my  volume  on  "  CEdema  "  are  correct,  why  in  the  "acidosis"  of  diabetes 
we  do  not  have  symptoms  of  nephritis  and  oedema.  In  answering  this 
several  facts  must  be  remembered.  First,  the  presence  of  some  abnormal 
acid  in  the  urine  does  not  yet  prove  that  the  actual  acidity  of  the  body  as 
a  whole  has  risen.  As  a  matter  of  fact  Yandell  Henderson  and  Frank  P. 
Underhill  [American  Journal  of  Physiology,  28,  275  (191 1)]  have  recently 
shown  that  m  the  "acidosis"  of  diabetes  just  the  reverse  is  probably  the 
case,  the  body  acidity  is  diminished.  Secondly,  in  cases  of  diabetes  in 
which  the  acid  intoxication  is  great  enough  we  do  have  casts  and  albumin 
in  the  urine.  Furthermore,  moderate  degrees  of  oedema  are  difficult  to 
discover  by  our  ordinary  rough  clinical  tests,  and  the  high  concentration  of 
sugar  present  in  the  cells  and  fluids  of  the  body  also  tends  to  reduce  this 
oedema,  for  while  the  non-electrolytes  do  not  reduce  appreciably  the  swell- 
ing of  certain  hydrophilic  colloids  in  low  concentrations  they  do  this  in  the 
higher  concentrations. 


NEPHRITIS  185 

proved  of  empirically,  as  evidenced  by  the  use  of  saline  pur- 
gatives, saline  diuretics,  etc.,  in  the  treatment  of  oedema, 
a  marked  reaction  against  the  giving  of  salts  in  oedematous 
states  has  more  recently  set  in.  Of  the  scores  of  salts  that 
might  have  been  attacked  in  this  way,  sodium  chloride  has 
been  especially  marked  out,  and  to-day  it  is  a  widely  ac- 
cepted behef  that  the  presence  of  this  particular  salt  in  the 
body  is  responsible  for  the  retention  of  water  and  so  the 
oedema  of  nephritis,  of  certain  cases  of  heart  disease,  etc. 
Evidence  for  the  support  of  such  a  view  has  been  entirely 
clinical.  It  has  been  noted  that  nephritic  individuals  with 
oedema  and  on  a  constant  diet  increase  in  weight  when 
sodium  chloride  is  added  to  their  food,  lose  again  when  this 
is  taken  away,  etc.  From  our  knowledge  of  the  general 
physicochemical  activities  of  the  salts  it  is  absolutely 
impossible  to  understand  why,  first  of  all,  sodium  chloride 
should,  of  all  the  common  salts  that  are  found  in  the  liv- 
ing organism,  act  in  this  specific  way,  and  second,  how  it 
accomplishes  the  results  that  are  claimed  for  it. 

In  order  to  satisfy  myself  as  to  whether  sodium  chloride 
(or  any  of  the  other  common  salts  found  in  our  tissues) 
really  has  any  such  specific  action  in  the  production  of 
oedema,  I  decided  to  test  the  matter  out  in  a  way  that  had 
not  yet  been  done,  and  which  was  freer  from  objection 
than  the  experiments  to  determine  this  point  that  have  been 
made  on  mammals.  For  experimental  purposes  I  used 
frogs  which  had  been  rendered  nephritic  by  being  injected 
with  uranium  nitrate  —  a  poison  which  is  generally  ac- 
knowledged as  one  of  the  best  for  the  production  of  ne- 
phritis experimentally.  By  placing  these  animals  in  water 
they  absorb  all  they  need  to  saturate  their  oedematous 
tissues  through  the  skin.  Normal  frogs  (practically)  do 
not  change  in  weight  when  kept  in  water.  Let  it  be  added 
that  these  frogs  were  really  nephritic  —  albumin  and  casts 


i86       ,  NEPHRITIS 

were  plentiful  in  th-e  urine,  and  the  tables  and  photographs 
illustrate  the  cedema'. 

Parenthetically  it  is  well  to  point  out  in  this  connection 
that  we  are  in  the  habit  of  considering  the  generahzed 
cedema  noted  in  nephritis  as  secondary  to  the  nephritis  — 
in  other  words  it  is  imagined  that  a  condition  capable  of 
producing  a  nephritis  first  reduces  the  function  of  the  kid- 
neys, and  because  of  this  an  oedema  of  the  body  tissues 
generally  results.  This  is  not  correct.  If  the  cedema  were 
secondary  to  the  loss  of  kidney  function  then  we  should  be 
able  to  produce  a  generalized  oedema  experimentally  most 
rapidly  by  complete  removal  of  the  kidneys.  As  a  matter 
of  fact,  nephrectomized  animals  either  develop  no  oedema  at 
all  or  only  a  very  sKght  one  when  compared  with  the  oedema 
developed,  say  after  the  injection  of  uranium  nitrate. 
This  shows  clearly  that  the  oedema  of  tJie  tissues  and  the  cede?na 
of  the  kidney  (nephritis)  arise  simultaneously,  and  from  the 
same  cause  —  the  uranium  nitrate  interferes  with  the  oxi- 
dation chemistry  in  all  the  tissues  of  the  body  at  once  and 
leads  to  an  abnormal  accumulation  of  acid  in  them.  In  the 
kidney  we  call  this  condition  nephritis;  in  the  body  tissues 
generally,  oedema;  in  the  eye,  glaucoma. 

As  the  following  experiments  show  very  clearly,  salts 
decrease  the  cedema  of  nephritis,  and  sodium  chloride  is  no 
exception  to  this  rule. 

Experiment  39.  —  Twelve  frogs  that  have  been  kept  in  jars  of 
tap  water  for  several  days  have  the  urine  squeezed  from  their  blad- 
ders, are  weighed,  and  divided  into  two  sets  of  six  each  in  such  a  way 
that  the  weight  of  any  one  frog  in  the  first  series  is  about  that  of  a 
corresponding  one  in  the  second  series.  They  are  then  all  injected 
with  0.2  gram  uranium  nitrate  into  the  dorsal  lymph  sac  and  placed 
in  separate  finger  bowls  each  containing  100  c.c.  distilled  water  in 
the  first  series  and  100  c.c.  Ringer  solution  in  the  second.  The 
fluid  in  the  bowls  is  changed  once  in  24  hours.  The  changes  in  the 
weights  of  the  frogs  are  indicated  in  the  following  tables: 


NEPHRITIS 


187 


» 


H 

^  H    0^  0» 

0    0    On  '^  04 
04     M     CO   '^ 

0 

0    CO         CO 

JvO  0  00    OnOO 
0^   H     M     04     CO 

+  +  +  + 

to 

0    0      M     t^    CO 

NO  NO    t^  t^CO 

\r> 

49            % 

53.5  (+  9.1) 

57        (+16.3) 

62        (+26.5) 

69       (+40.8) 

dead 

•^ 

0  00 
b?  0  6 

t+t 

to 

04      M    NO 

Tt  to  to 

CO 

t^  0    04   to 

vOCO    6    M    t-> 

to^    OI     Tt    T:f    t;1-_^ 

+  +  +  +  I 
to         ^       '^ 

0    M  0  0    On 
"^  to  to  to  10 

c< 

±±2 

to 

to  O)     tJ- 
CO  ^  '^ 

H 

CO  On  0 
vO  CO  CO  CO 

0^    CO    ^    Ttr^ 

to 

1 

0   to  10  C 

CO    M      M      (W 

•:> 

0  00    0    ^CC 

M    rJ-NO  OC 

^ 


If 

0     0     l>.NO 

0    t^-  O^00     CO 
M     04      fO 

> 

0    to  04    CO 

>^  00  M    On  CO 
0^         01    01    ro 

+  +  +  + 

to  l~-»  0\  ':t  r^ 
NO  0   t^CO  00 

> 

00  .<t  0  0 

>jO  ^  CO  oo  t/-> 

0^              H      04      04   rrt 

±+±±s 

'a 

to 

<^    -^   On  Tt-  to 

to  to  too  0 

> 

1— 1 

o'^o't^ 

«^             04      OJr^ 

to 

C4    0     M     00 

T}-  t1-  to  10 

- 

0  0    On  0 

vo  "sho  0  to 

t)\            M     oo   CO 

++++ 

04      T}-     ON    to    t^ 

rf  -^  "^  to  to 

K 

On  to  CO  CO 

jsOOO    0    CO  CO 
<i\           04     CO   CO 

+  +  +  + 

to 

On  04    r>.  04    01 
TO  ■^  ■*  to  to 

- 

•^  -"^  CO  CO 

IsP    00   04     M     0 

O^    M     04     CO   ^rrt 

ttttt 

to 

COOO      H     Th    J>. 

CO  CO  Tj-  Tl-  '^l- 

1 

0  to  to  0 

_      CO    MM      CO 

0  00    0    Tl-  00 

H    '^O  CO 

i88  NEPHRITIS 

Experiment  40.  —  Six  frogs  are  weighed,  each  injected  with  0.05 
gram  uranium  nitrate  into  the  dorsal  lymph  sac,  and  divided  into  two 
sets  of  three  each.  Those  of  the  first  are  kept  in  separate  finger 
bowls,  each  containing  100  c.c.  water;  those  of  the  second  in  bowls 
containing  100  c.c.  |  molecular  sodium  chloride  solution.  The 
changes  in  weight  observed  are  as  follows: 

Series  in  Water. 


Hours. 

I 

2 

3 

0 
18 
26 
42 
68 
92 

30    % 

33  (+10.0)  ' 

36  (+20.0) 

37  (+23.3) 

38  (+26.6) 

39  (+30.0) 

27     % 

.  ? 

'  30.5  (+12.9) 

35   (+29-6) 

41   (+51.8) 

dead 

24       % 

28  (+16.6) 

29  (+20.8) 
29.5  (+22.9) 
? 

30  (+25.0) 

Series  in  \  Molecular  NaCl  (0.975%). 


Hours. 

I. 

II. 

III. 

0 
18 
26 
42 
68 
92' 

34    % 

32  (-  5-8) 

33  (-  2.9) 
33   (-  2.9) 

38  (+11. 7) 

39  (+14.7) 

29    % 

29  (+  0) 

30  (+  3-4) 

31  (4-  6.8) 
33  (+13-8) 
35  (+20.7) 

26    % 

26  (+  0) 

27  (+  3-8) 

28  (+  7.7) 
30  (+15-3) 

dead 

The  effect  of  the  sodium  chloride  in  reducing  the  oedema 
is  evident  to  mere  inspection.  In  Fig.  30,  a  and  h,  is  shown 
frog  3  of  Experiment  40,  photographed  at  the  time  of  in- 
jection and  42  hours  later.  Figure  31,  a  and  6,  shows  frog 
III  similarly  photographed. 

Are  we  now  to  conclude  that  the  observations  are  wrong 
of  those  who  have,  by  careful  methods,  noted  an  increase  in 
weight  (increase  in  oedema)  after  the  feeding  of  salts,  par- 
ticularly sodium  chloride,  to  patients  afflicted  with  oedema? 
Not  necessarily,  though  it  must  be  said  that  grave  objec- 
tions may  be  raised  against  many  of  the  clinical  studies  of 
this  subject. 


NEPHRITIS 


189 


1 90 

L 

NEPHRITIS 

c 


NEPHRITIS  191 

When  one  studies  carefully  the  cases  in  the  literature  in 
which  salts  have  been  found  to  increase  oedema,  one  notes 
the  fact  that  these  are  for  the  most  part  such  as  have  been 
afHicted  with  ascites,  hydrothorax,  etc.  When  now  any 
salt  is  given  such  an  individual  his  tissues  may  very  well 
give  up  water  as  do  the  frogs  that  have  just  been  de- 
scribed. But  where  does  the  water  go?  The  body  weight 
as  a  whole  can  diminish  only  if  this  water  is  lost  from  the 
body  through  the  urine  (skin,  gastro-intestinal  tract,  or 
lungs).  But  in  nephritis  the  kidney  does  not  so  readily 
rid  the  body  of  water  as  in  health,  and  so  this  water 
must  go  somewhere  else.  If  it  does  not  come  out  through 
some  other  emunctory  (as  in  the  diarrhoeal  stools  at 
times  observed  in  nephritis),  this  water  can  only  escape 
into  the  cavities.  What  happens  here  is  identical  with 
the  development  of  ascites,  etc.,  in  our  experimental  ani- 
mals when  we  make  these  (especially  after  first  render- 
ing them  oedematous  by  any  means  we  choose)  very 
rapidly  give  up  their  water  by  injecting  a  concentrated 
salt  solution. 

I  saw  a  good  clinical  illustration  of  this  in  a  patient  of 
W.  S,  Kuder.  A  woman  who  for  several  weeks  had  been 
in  bed,  suffering  from  an  extensive  generalized  oedema, 
with  collections  of  fluid  in  the  pleural  cavities  and  abdomen, 
secondary  to  a  heart  muscle  insufficiency  of  several  years 
duration,  had  the  abdominal  effusion  removed  by  para- 
centesis. In  order  to  keep  up  the  drainage  some  strands 
of  silk  were  left  in  the  opening  made  by  the  trocar.  Seep- 
age stopped  at  the  end  of  twenty-four  hours,  but  the 
silk  was  left  in  place.  On  the  third  day  a  liter  of  water 
containing  14  grams  of  sodium  chloride  and  10  grams  of 
crystallized  sodium  carbonate,  was  given  intravenously  to 
combat  the  tissue  oedema.  This  went  down  enormously, 
and  as  it  disappeared  the  abdominal  wound  began  to  seep 


192 


NEPHRITIS 


once  more,  so  that  pad  after  pad  had  to  be  applied  to  the 
abdomen  to  absorb  the  liquid. 

It  is  clear  therefore  that  while  the  oedema  of  the  tissues 
is  reduced,  when  salts  or  alkali  are  given  an  cedematous  in- 
di\ddual,  the  collection  of  fluid  in  the  cavities  is  increased. 
When  now  we  deal  with  a  clinical  case,  the  thirst  ^  (from 
which  the  animals  also  suffer)  leads  the  patient  to  drink 
water  and  so  his  total  body  weight  (which  in  turn  is 
taken  as  a  measure  of  his  oedema)  increases. 

But  such  a  secretion  of.  fluid  into  the  peritoneal  or  other 
cavity  would  not  by  itself  be  a  particularly  serious  thing, 
nor  does  this  alone  explain  what  happens  in  a  persistent 
ascites.  As  we  have  long  known,  alike  from  experiment 
and  from  clinical  observation,  water  and  various  salt  solu- 
tions are  readily  absorbed  from  the  peritoneal  (and  other 
serous)  cavities.  And  yet  the  ascitic  fluid  is  not  absorbed. 
Why  not?  E\^dently,  after  water  or  a  salt  solution  has 
been  secreted  into  the  peritoneal  or  other  cavity  something 
must  happen  to  this  fluid  which  prevents  its  reabsorption. 
What  this  something  is,  is  that  albumin  is  added  to  it. 
Why  this  renders  the  ascitic  fluid  unabsorbable  is  appar- 
ent when  the  following  considerations  are  borne  in  mind. 
With  the  origin  of  the  albumin  we  are  not  immediately 
concerned,  though  it  is  of  interest  to  recall,  after  what 
was  said  regarding  the  origin  of  albumin  in  the  urine, 
that  the  ascitic  fluid  may  be  looked  upon  as  an  albumin- 
containing  secretion  from  the  peritoneal  tissues  which,  in  its 
general  composition  and  mode  of  origin,  finds  an  analogue 
in  the  highly  albuminous  urine  secreted  by  the  kidney  in 
acute  nephritis. 

1  Living  animals  and  plants  do  not  behave  passively  toward  an  abstrac- 
tion of  water.  As  soon  as  this  occurs  conditions  develop  in  the  cells  which 
increase  their  avidity  for  water.  Certain  plants,  for  example,  begin  to  de- 
velop acid  as  soon  as  we  try  to  abstract  water  from  them  by  any  means. 
Animals  behave  similarly  when  they  are  robbed  of  their  water. 


NEPHRITIS  193 

As  outlined  in  the  discussion  of  our  experiments  on 
urinary  secretion,  special  emphasis  must  be  laid  upon  the 
fact  that  only  '^  free "  water  is  secreted  by  the  kidney. 
The  water  of  the  blood  is  not  ''  free  "  but  is  combined  with 
the  colloids  of  the  blood.  This  water  is  not  available  for 
urine  until  it  is  freed  from  the  colloids  of  the  blood.  The 
water  of  the  blood  becomes  available  for  absorption  (and 
subsequent  secretion)  by  any  tissue  only  as  this  tissue  is 
first  able  to  set  the  water  free  from  the  colloids  of  the 
blood  and  lymph  or  as  the  blood  and  lymph  themselves 
suffer  changes  which  make  them  yield  up  some  of  their 
water.  Only  such  "  free  "  water  can  be  available  for  urine 
and  conversely  it  is  only  because  the  water  in  the  blood  is 
held  in  combination  by  the  colloids  here  that  not  all  the  blood 
and  lymph  are  absorbed  from  their  respective  vessels  by  the 
tissues.^  The  colloids  of  the  blood  keep  the  water  in  the 
blood  and  prevent  its  total  absorption  by  the  tissues. 
When  now  we  recall  the  fact  that  except  for  the  presence 
of  the  red  blood  corpuscles,  blood  and  lymph  are  practically 
identical  in  composition,  and  that  the  so-called  transudates 
in  ascites,  hydrothorax,  etc.,  are  identical  with  lymph,  then  we 
have  no  difficulty  in  understanding  why  these  too  may  persist 
for  days,  weeks,  or  months  in  the  body  cavities  without  being 
absorbed.  They  are  colloidal  solutions  in  which  the  solvent  is 
bound  to  the  colloid,  and  not  until  the  solvent  is  rendered 
^^  free  "  can  it  be  absorbed."^ 

1  It  is  because  no  adequate  (hydrophilic)  colloidal  solution  has  as  yet 
been  prepared  that  we  are  still  far  from  possessing  a  perfusion  liquid  that 
will  act  better  than  our  present  "physiological "  salt  solutions  in  haemorrhage, 
certain  poisonings,  and  shock.  James  J.  Hogan  and  I  will  shortly  discuss 
the  theoretical  and  experimental  foundations  for  the  preparation  of  such 
solutions  in  another  place.  See  for  a  discussion  of  the  factors  involved  in 
shock  Yandell  Heftderson's  excellent  papers,  especially  Am.  Jour.  Physiol. 
27,  167  (1910). 

2  Certain  experiments  of  R.  Heidenhain,  E.  W.  Reid,  and  0.  Cohnheim 
might  lead  one  to  think  that  animals  do  absorb  their  own  blood  and  lymph 


194  NEPHRITIS 

In  order  to  show  that  such  colloidal  solutions  can,  as  a 
matter  of  fact,  not  be  absorbed  we  need  but  recall  how 
blood  extravasations  and  lymph  introduced  into  the  perito- 
neal ca\ity,  even  in  entirely  healthy  animals,  may  remain 
here  unchanged  and  undiminished  in  amount  for  periods  of 
time  in  w^hich  other  aqueous  solutions  not  containing  such 
colloidal  material  (which  in  other  words  contain  ''  free " 
water)  are  readily  absorbed.  The  following  experiments 
prove  this  very  clearly. 

Experiment  41.  —  A  black  and  white  rabbit  is  taken  from  his 
hutch,  catheterized,  and  then  weighed.  His  weight  is  found  to  be 
1493  grams.  A  shght  opening  is  made  in  the  abdominal  wall  and 
traction  made  on  this  so  as  to  make  the  entrance  of  fluid  into  the 
peritoneal  cavity  easy.  A  second  rabbit  has  the  carotid  laid  bare  for 
as  great  a  distance  as  possible  in  the  neck.  It  is  ligated  high  up,  an 
artery  forceps  is  attached  to  the  coat  of  the  vessel,  a  Langeiiheck  forceps 
is  placed  below  this,  and  the  carotid  is  severed.  This  second  animal  is 
now  placed  in  such  a  position  that  the  blood  will  flov:  directly  from 
his  carotid  into  the  abdominal  cavity  of  the  first  animal  when  the 
Langenheck  forceps  is  removed.  The  blood  passes  in  a  stream  directly 
from  the  cut  artery  of  the  second  animal  into  the  peritoneal  cavity  of 
the  first.  This  procedure  is  carried  out  at  2.40  p.m.  The  abdominal 
wound  is  closed  immediately  and  the  animal  is  weighed  a  second 
time  to  see  how  much  blood  has  flowed  in.  The  second  weighing 
registers  1504  grams,  which  means  that  11  grams  of  blood  have 
flowed  in.  At  the  end  of  an  hour  the  animal  is  killed  by  a  blow 
on  the  head  and  immediately  autopsied.  The  blood  is  found  unco- 
agulated  in  the  folds  of  the  intestine.  It  is  carefully  aspirated  into 
a  tared  flask  and  weighed.     11  grams  of  blood  are  recovered. 

Experiment  42.  —  In  an  entirely  similar  way  a  guinea  pig, 
weighing  520  grams,  has  a  small  opening  made  in  its  abdomen,  and 
the  blood  from  the  carotid  of  a  rabbit  is  made  to  flow  directly  into 
it.  An  increase  in  the  weight  of  the  guinea  pig  of  2.2,  grams  is 
thereby  brought  about.     At  the  end  of  ij  hours  the  pig  is  killed  by 

as  such.  This  is  not  the  case.  For  a  discussion  of  this  problem  and  a  crit- 
icism of  the  experinrents  of  Heidenhain,  Reid  and  Cohnheim  see  my  paper 
on  absorption  and  secretion.     Kolloidchemische  Beihefte,  2,  304  (1911). 


t 


NEPHRITIS  195 

a  blow  on  the  head  and  the  unabsorbed  blood  is  aspirated  into  a 
tared  flask.     2.1  grams  are  recovered. 

Experiment  43,  —  A  black  and  white  rabbit,  weighing  1630.5 
grams,  receives  intraperitoneally  in  the  already  described  way  enough 
blood  from  the  carotid  of  a  second  rabbit  to  raise  the  weight  of  the 
former  26.0  grams.  At  the  end  of  an  hour  the  rabbit  is  killed,  and 
the  unabsorbed  blood  is  carefully  recovered  by  aspiration  into  a  tared 
flask.     26.0  grams  of  blood  are  recovered. 

Experiment  44.  —  A  white  rabbit,  weighing  767  grams,  receives 
intraperitoneally  45  grams  of  blood  from  the  carotid  of  a  Belgian 
hare.  At  the  end  of  70  minutes  the  animal  is  killed  by  a  blow  on  the 
head  and  the  blood  found  in  the  peritoneal  cavity  is  aspirated  into  a 
tared  flask.     42.2  grams  are  recovered. 

As  the  impression  might  be  obtained  that  the  failure  of 
an  animal  to  absorb  its  own  blood  is  connected  in  some 
way  with  the  nature  of  blood  itself,  and  not  merely  with 
the  fact  that  this  is  a  solution  in  which  all  the  water  is  held 
in  combination  with  a  colloid  and,  therefore,  simply  cannot 
be  absorbed  until  first  separated  from  the  colloid,  it  was 
necessary  to  repeat  this  experiment  with  a  colloidal  solution 
other  than  blood.  The  result  obtained  with  natural  white- 
of-egg  follows.  In  a  similar  way  it  can  be  shown  that  cubes 
of  agar-agar  do  not  lose  in  weight,  and  that  gelatine  solu- 
tions are  absorbed  only  very  slowly  (not  until  the  gelatine 
is  ''  digested  "  and  so  loses  its  colloid  character). 

Experiment  45.  —  Into  the  peritoneal  cavities  of  two  guinea  pigs, 
weighing  respectively  537  and  563  grams,  are  injected  by  means  of  a 
large  aspirating  syringe  respectively  20.8  c.c.  and  31.2  c.c.  white-of- 
egg  (natural).  At  the  end  of  an  hour  they  are  killed  by  a  blow  on  the 
head  and  the  unabsorbed  peritoneal  contents  are  aspirated  into  tared 
flasks.     18.4  c.c.  are  recovered  from  the  first,  27.7  c.c.  from  the  second. 

In  concluding  this  argument  it  is  only  necessary  to  show 
what  is  a  familiar  fact  in  physiology,  that  under  identical 
conditions,  water  and  salt  solutions  are  readily  absorbed 
(because  they  contain  ''free"  water). 


196  NEPHRITIS 

Experiment  46.  — Three  guinea  pigs,  weighing  respectively  417, 
397,  and  419  grams,  are  each  injected  intraperitoneally  with  20.8  c.c. 
respectively  of  water,  1^2  and  \  molecular  NaCl  solution.  At  the  end 
of  an  hour  the  unabsorbed  fluid  is  recovered  and  found  to  measure 
respectively  5.4,  11.8,  and  13.0  c.c. 

From  what  has  been  said  it  must  be  clear  that  little 
justification  exists  for  the  exclusion  of  sodium  chloride,  as 
for  the  exclusion  of  any  other  of  the  ordinary  salts  found  in 
the  body  tissues,  from  the  diet  with  the  thought  of  thereby 
relieving  the  oedema  of  nephritis.  Such  a  procedure  does 
just  the  reverse.  We  have  seen  how  the  only  untoward 
action  of  giving  salts  might  reside  in  an  increase  of  ascites, 
hydrothorax,  etc.  When  such  accumulations  of  fluid  in  the 
cavities  become  sufficiently  great  to  demand  attention  on 
their  own  account,  then  we  have  to  bear  in  mind  that  their 
composition  is  of  such  a  character  as  to  render  their  ab- 
sorption without  antecedent  change  (digestion  of  the  protein 
colloids,  reduction  of  their  affinity  for  water)  impossible. 
Clearly,  the  thing  to  do  then  is  to  tap. 

Nor  is  there  anything  strange  in  the  fact  that  the  re- 
moval of  a  comparatively  small  amount,  say  of  an  ascitic 
accumulation,  may  be  followed  by  a  rapid  absorption  of 
the  rest.  As  the  amount  of  fluid  in  a  serous  cavity  in- 
creases, the  circulation  through  the  surrounding  tissues  be- 
comes more  and  more  embarrassed,  and  so  the  possibilities 
for  absorption  progressively  poorer.  To  relieve  this  pressure 
even  somewhat  wiU  improve  the  circulation,  not  alone  as 
to  quantity  but  as  to  quahty  of  blood  passing  through  the 
part  (a  blood  more  nearly  arterial  in  character  replacing  one 
highly  venous  in  character),  and  so  by  favoring  the  removal 
of  CO2  and  other  acids  always  found  in  such  serous  accumu- 
lations^ decrease  the  power  of  the  colloids  here  for  holding 

1  G.  Slrasshurg:  Pfliiger's  Arch.,  6,  65  (1872);  A.  Ewald:  Arch.  f.  (Anat. 
u.)  Physiol.,  1873,663;  Felix  Iloppe-Seyler:  Physiologische  Chemie,  1,  601. 
Berlin,  1877. 


NEPHRITIS  197 

water,  and  so  bring  about  further  opportunity  for  the  ab- 
straction of  water  ^from  the  transudates  found  in  these 
cavities.  What  holds  for  the  ''transudates"  and  their  ab- 
sorption holds  also,  of  course,  for  the  absorption  of  inflam- 
matory ''exudates." 


From  what  has  been  written  in  this  volume,  it  is  clear  that 
we  have  held  the  evidence  to  indicate  that  nephritis  results 
from  any  condition  or  combination  of  conditions  which  lead 
to  the  abnormal  production  or  accumulation  of  acid  in  the 
kidney,  and  the  action  of  this  acid  upon  a  series  of  such 
colloidal  structures  as  characterize  those  found  in  the  kidney. 
From  these  considerations  we  have  then  tried  to  obtain  an 
"explanation"  of  the  various  phenomena  which  serve  to 
characterize  nephritis  from  a  physiological  and  a  morpho- 
logical standpoint.  The  question  now  arises  whether  the 
acid  factor  is  the  only  one  concerned  in  producing  the 
picture.  This  does  not,  of  course,  follow.  Any  condition 
present  in  the  kidney  and  capable  of  exerting  an  action  like 
that  of  an  acid  could  add  itself  to  the  acid  factor.  What 
all  such  are  or  may  be  it  would  be  purposeless  to  count  up, 
—  they  are  the  factors  which  we  know  now,  or  may  discover, 
to  be  effective  in  influencing  the  physical  state  of  the  body 
colloids,  —  but  as  a  striking  illustration  we  might  mention 
the  ferments.  Not  only  do  the  proteolytic  ferments,  for 
example,  bring  about  a  splitting  of  the  protein  molecule 
which  is  similar  or  identical  with  the  splitting  produced  by 
acids,  but  certain  antecedent  physical  changes  produced  in 
the  colloids  by  the  action  of  the  two  are  also  identical,  a 
point  which  Wolfgang  Pauli  ^  has  recently  emphasized  from 
a  physicochemical  point  of  view  in  a  way  that  gives  it  a 
special  interest  biologicaUy. 

^  Wolfgang  Pauli:  Pfliiger's  Archiv,  136,  495  (1910). 


198  NEPHRITIS     .      . 

With  this  we  will  end  for  "the  present  our  discussion  of 
nephritis,  and  our  attempt  to  find  a  unifying  interpretation 
for  the  myriad  facts  bearing  upon  its  nature  and  cause, 
that  fourscore  years  and  a  thousand  workers  have  left  us 
as  a  lavish  heritage. 


AUTHOR    INDEX. 


Abderhalden,  Emil,  126. 

Adams,  L.  P.,  163. 

Araki,  Trasaburo,  44,  48,  49,  50, 

Barcroft,  107,  III,  131. 
Bechhold,  H.,  106. 
Berghausen,  Oscar,  50,  150. 
Bowman,  W.,  32,  58. 
Bradford,  102. 

Brodie,  T.  G.,  107,  iii,  131. 
Buchner,  51. 
Bugarszky,  S.,  23. 
Bunge,  G.  von,  126. 
Burton-Opitz,  100. 

Clark,  W.  A.,  167. 
Cohnheim,  Julius,  62,  193,  194. 
Cohnheim,  Otto,  104. 

Dreser,  H.,  27,  28,  29,  30,  32, 

123. 
Duclaux,  51. 
Dunham,  H.  K.,  162,  163. 

Edlefson,  G.,  44. 
Eichberg,  J.  H.,  174. 
Ewald,  A.,  48,  196. 

Farkas,  G.,  22. 
Fihe,  C.  C,  173. 
Fischer,  M.  H.,  50,  61,  73,  104, 

no.  III,  115,  150,  157. 
Fletcher,  44. 
Fraenkel,  22. 
Frerichs,  57. 
FreundHch,  H.,  8. 

Geier,  O.  p.,  164. 
Gettler,  A.  O.,  126. 
Gies,  W.  J.,  184. 
Goodridge,  F.  G    184. 
Gottheb,  106. 
Graham,  Thomas,  3,  7. 
Griitzner,  30,  33. 
Guthrie,  C.  C,  179. 


Halliburton,  75.  ' 
Hamburger,  H.  J.,  63,  72,  73,  104. 
52.      Hamilton,  Jo.,  175. 

Hamilton,  N.  A.,  169. 

Hammarsten,  O,,  75. 

Handovsky,  H.,  78,  100. 

Hardy,  W.  B.,  100. 

Hart,  E.  B.,  75. 

Heidenhain,  R.,  3,  27,  30,  31,  32,  33, 

34,  104,  105,  107,  123,  193,  194. 
Henderson,  L.  J.,  22. 
Henderson,  Yandell,  184,  193. 
Herrmann,  Max,  50,  150. 
Hober,  R.,  22,  24,  104. 
Hogan,  James  J.,  160,  161,  162,  173, 

193; 

Hopkins,  44. 

Hoppe-Seyler,  F.,  49,  51,  196. 

34,      Irasawa,  T.,  49. 


Jaksch,  R.  von,  26,  49. 

Kiely,  W.  E.,  173. 

Kiliani,  H.,  51. 

Kraus,  F.,  26. 

Kuder,  W.  S.,  173,  175,  191. 

Landsteiner,  63. 
Laqueur,  E.,  75. 
Leube,  W.,  44. 
Liebermann,  23. 
Ludwig,  Carl,  32. 

Magnus,  105,  106. 
Majors,  E.  A.,  172. 
Mandel,  J.  A.,  75. 
Meisenheimer,  51. 
Mendel,  E.,  49. 
Meyer,  Hans,  114. 
Miinzer,  E.,  49. 

Nef,  J.  U.,  SI. 
Noorden,  C.  von,  44. 
Noyes,  A.  A.,  7. 
Nussbaum,  27,  30,  123. 


109, 


199 


200 


AUTHOR  INDEX 


OSBORXE,  W.  A.,  75. 

Ostwald,  Wolfgang,  8. 
Overton,  E.,  104,  114. 

Palma,  p.,  49. 

Pauli,  Wolfgang,  75,  78,  100,   109, 

197. 
Peiper,  E.,  26. 
Pemsel,  W.,  23. 
Perrin,  J.,  8. 
Ponfick,  105. 

Reid,  E.  Waymouth,  104,  193,  194. 
Rhorer,  Ludwig  von,  24. 
Rindfleisch,  E.,  62. 
Robertson,  T.  B.,  23,  75. 
Rumpf,  W.  H.,  26. 

Sackur,  O.,  75. 
Schade,  51. 
Schloss,  Ernst,  126. 
Schmidter,  W.  C,  162. 
Schoep,  Alfred,  107. 
Schorr,  Karl,  78. 
Schroeder,  P.  von,  100. 


Schiitzenberger,  51. 
Sherman,  H.  C,  126. 
Sjoquist,  23. 
Slyke,  L.  L.  van,  75. 
Smith,  Dudley,  165. 
Spiro,  K.,  23. 
Starling,  E.  H.,  104. 
Strassburg,  G.,  48,  196. 

Tait,  Dudley,  97. 
Terray,  P.  von,  48. 
Thompson,  G.,  48. 
Traube,  Isador,  108. 
Tuechter,  J.  L.,  164. 

Underhill,  F.  p.,  184. 

ViRCHow,  R.,  52,  61,  62. 

Weigert,  57. 
Woodyatt,  R.  T.,  51. 
WooUey,  Paul  G.,  77. 

Zillessen,  Hermann,  48,  50. 
Zuntz,  53. 


SUBJECT    INDEX. 


Acid,  2, 125;  as  cause  of  albuminuria, 
20;  effect  of,  on  kidney,  35,  125;  in 
nephritis,  125;  in  oedema,  184. 

Acidity,  of  normal  urine,  24;  of 
nephritic  urine,  25. 

Acidfuchsin,  27,  123. 

Acidosis,  184. 

Albumin,  in  effusions,  192;  absorp- 
tion of  solutions  containing,  193, 

Alhumimma,  definition  of,  i;  cause 
of,  2;  after  injection  of  acid,  35; 
after  injection  of  alkali,  40;  after 
hard  work,  44,  45,  18°;  in  heart 
disease,  47;  in  lung  disease,  47; 
in  anaemia,  48;  in  epilepsy,  48; 
after  exposure  to  cold,  49;  after 
interference  with  blood  supply, 
50;  after  intoxication,  51;  of  the 
newborn,  52;  after  salt  restriction, 
53;  after  excessive  consumprion  of 
water,  53;  hypertrophy  of  heart 
and,  98;  treatment  of,  125. 

Anamia,  albuminuria  in,  48;  due  to 
nephritis,  127. 

Arsenic  oedema,  173. 

Arteriosclerosis,  97,  173,  176. 

Ascites,  191. 

Asthma,  173.  .re 

Athletes,  albuminuria  in,  44;  rehef  of 
albuminuria  in,  180. 

Basket-hall,  45,  i8o>  181,  182. 

Blood,  physicochemical  characteris- 
tics of,  5;  reaction  of,  21;  in 
nephrids,  26;  absorption  of,  193. 

Blood  corpuscles,  diapedesis  of  red, 
78;  migration  of  white,  81. 

Blood  pressure,  100. 

Brain  oedema,  173. 

Bronchial  asthma,  173. 

Case  reports,  of  nephritis,  161. 
Casein,  75. 

Casts,  origin  of,  84;  types  of,  88; 
significance  of,  92. 


Cavities,  collection  of  fluid  in,  191, 

193- 

Chronic  interstitial  jiephritis,  58,  94, 
176,  177;  water  output,  in,  95;  and 
nitrites,  177. 

Classification  of  colloids,  7. 

Cloudy  swelling,  61. 

Coefficient  of  distribution,  114. 

Colitis,  mucous,  173. 

Colloids,  7,  83;  classification  of,  7,  8; 
absorption  of  dyes  by,  119;  in 
perfusion  liquids,  193;  absorption 
of  solutions  containing,  194. 

Crystalloids,  7. 

Diabetes,  184. 

Diapedesis,  78. 

Diet,  in  nephritis,  125. 

Distribution  coefficient,  114. 

Diuretics,  158. 

Dyes,  absorption  of,  by  colloids,  119. 

Eclampsia,  161,  163,  165,  167,  168, 

169,  172,  177. 
Emulsion  colloids,  8. 
Epilepsy,  albuminuria  in,  48. 
Exercise,  albuminuria  after,  44. 
Exudates,  191,  193,  196. 

Ferments,  197. 

Fibrin,  solution.of,  9;  swelling  of,  12, 

184. 
Filtration,  105. 

Food,  in  treatment  of  nephritis,  125. 
Free  water,  193. 

Gel,  8. 

Gelatine,  solution  of,  15. 

Glaucoma,  173. 

Hcemoglobinuria,  49,  127. 

Hemolysis,  49,  127. 

Hemorrhage,  by  diapedesis,  78;  per- 
fusion in,  193. 

Hay  fever,  173. 

Heart,  albuminuria  in  diseases  of, 
47;  oedema  in  diseases  of,  173,  191. 


202 


SUBJECT  INDEX 


Hydrothorax,  191,  193. 
Hypertrophy  of  heart  in  nephritis,  98. 

Injections  of  alkali  and  salt,  161;  by- 
rectum,  162,  163,  164,  165,  166, 
169,  172,  173,  175;  intravenously, 
168,  170,  173,  175,  178. 

Kidney,  physicochemical  structure 
of,  5;  staining  of,  27,  123;  mor- 
phological changes  in,  56;  small 
red,  60;  small  gray,  60;  cloudy 
swelling  of,  61;  secretion  of  water 
by,  102;  secretion  of  dissolved  sub- 
stances by,  113. 

LeukcBmia,  albuminuria  in,  48. 
Ligation,  of  kidney  vessels,  50,  124. 
Lipoids,  115. 

Lung,  albuminuria  in  diseases  of,  47. 
Lymph,  absorption  of,  193. 

Marasmus,  173. 

Milk,  179. 

Membrane,  urinary,  6,  109. 

Mucous  colitis,  173. 

Nephritis,  definition  of,  i;  cause  of, 
2;  after  injection  of  acid,  35;  after 
injection  of  alkali,  40;  after  hard 
work,  44;  in  heart  disease,  47;  in 
lung  disease,  47;  in  anaemia,  48; 
in  epilepsy,  48;  after  exposure  to 
cold,  49;  after  interference  with 
blood  supply,  50;  after  intoxica- 
tion, 51;  of  the  newborn,  52;  after 
salt  restriction,  53;  parenchyma- 
tous, 57,  173,  174;  chronic  inter- 
stitial, 58,  94,  176;  water  secretion 
in,  95;  arteriosclerosis  and,  97, 
173,176;  hypertrophy  of  the  heart 
and,  98;  blood  pressure  in,  100; 
night  urination  in,  loi;  treatment 
of,  125;  water  in,  127;  salts  in,  134, 
161,  180;  clinical  reports  of,  160; 
of  pregnancy,  161,  163,  165,  167, 
168,  169,  172;  sodium  carbonate 
in,  161;  stripping  of  capsule  for, 
178;  milk  in,  179;  prevention  of, 
179;  citrus  fruit  in,  180;  in  frogs, 
185. 

Neutral  red,  121. 

Neutrality,  maintenance  of,  in  tis- 
sues, 22. 

Nitrites,  177, 


(Edema,  of  brain,  173;  after  arsenic 
injections,  173;  treatment  of,  183; 
and  salt  restriction,  183;  criticism 
of  theory  of,  184. 

Partition  coefficient,  114. 
Paroxysmal  hcemoglohinuria,  49,  127. 
Perfusion  mixtures,  178,  179,  193. 
Pernicious  ancemia,  albuminuria  in, 

48. 
Plants,  reaction  of,  to  loss  of  water, 

192. 
Pregnancy  nephritis,  161,  163,  165, 

167,  168,  169,  172. 
Protein  gels,  solution  of,  9. 
Proteins,  9,  126. 

Reaction^  of  blood,  21,  26;  of  tissues, 
21,  26;  of  normal  urine,  24;  of 
nephritic  urine,  25,  27. 

Red  blood  corpuscles,  diapedesis  of, 

78. 

Salts,  in  treatment  of  nephritis,  134; 
in  treatment  of  oedema,  183. 

Salt  restriction,  albuminuria  of,  53; 
in  nephritis,  134;  and  salt  elimi- 
nation, 180;  and  oedema,  183. 

Scarlet  fever,  162. 

Shock,  193. 

Selective   absorption   and   secretion, 

115- 
Secretion,  34;  disturbances  in,  93;  of 

dissolved  substances,  113. 
Serous  cavities,  191,  193,  196. 
Serous     elusions,    191,     193,     196; 

acids  in,  196. 
Stnall  red  kidney,  60. 
Small  gray  kidney,  60. 
Sodium  carbonate,  in  nephritis,  161; 

preparation  of  solutions  of,   178; 

dried,    178;   cr>'stallized,    178;   in 

oedema,  191. 
Sodium  chloride,  in  nephritis,    134, 

161;  in  oedema,  185,  191. 
Sodium  indigosulphonate,  30,  121. 
Sol,  83. 

Stains,  absorprion  of,  by  colloids,  119. 
Staining  of  kidne}^    27,    123;  with 

acid    fuchsin,    27;    with    sodium 

indigosulphonate,  30. 
State,  colloidal  and  crj'^stalloidal,  7. 
Suppression  of  urine,  161,  162,  163, 

164,  165,  166,  172. 
Suspension  colloids,  8. 


SUBJECT  INDEX 


203 


Tapping,  iq6. 

Therapy,  see  Treatment. 

Tissues,  neutral  reaction  of,  21. 

Toluidin  blue,  119. 

Tonsillitis,  164. 

Transudates,  197. 

Treatment,    of    paroxysmal    haemo- 

globinuria,  49;  of  nephritis,  125; 

of  oedema,   183. 

Urcemia,  26,  176. 

Urinary  secretion,  theories  of,  104; 
selective  character  of,  115. 

Urinary  membrane,  6,  109. 

Urine,  physical  chemistry  of,  6;  re- 
action of,  23;  acidity  of  normal, 
24;  acidity  of  nephritic,  25;  sup- 


pression of,   161,   162,   163,   164, 
165,  166,  172. 
Urticaria,  126. 

Vomiting,  of  pregnancy,  173;  in 
pregnancy  nephritis,  166,  168,  169. 

Water,  albuminuria  following  con- 
sumption of,  53;  secretion  of,  by 
nephritic  kidney,  102;  theories  of 
secretion  of,  104;  in  treatment  of 
nephritis,  129,  161;  of  the  blood 
and  lymph,  193. 

White  blood  corpuscles,  migration  of, 
81. 

Work,  albuminuria  after,  44;  and 
nephritis,  127,  180. 


Short-title  Catalogue 

OF    THE 

PUBLICATIONS 

OF 

JOHN  WILEY  &  SONS 

New  York 
London:   CHAPMAN    &  HALL,  Limited 


ARRANGED    UNDER   SUBJECTS 


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3 


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Jackson's  Directions  for  Laboratory  Work  in  Physiological  Chemistry.  .8vo,  1  25 

Lassar-Cohn's  Praxis  of  Urinary  Analysis.      (Lorenz.) 12mo,  1  00 

Mandel's  Hand-book  for  the  Bio-Chemical  Laboratory 12mo.  1  50 

*  Nelson's  Analysis  of  Drugs  and  Medicines l2mo,  3  00 

*  Pauli's  Physical  Chemistry  in  the  Service  of  Medicine.      (Fischer.) .  .12mo,  1  25 

*  Pozzi-Escot's  Toxins  and  Venoms  and  their  Antibodies.      (Cohn.).  .  12mo,  1   00 

Rostoski's  Serum  Diagnosis.      (Bolduan.) 12mo,  1  00 

Ruddiman's  Incompatibilities  in  Prescriptions Svo,  2  00 

Whys  in  Pharmacy 12mo,  1   00 

Salkowski's  Physiological  and  Pathological  Chemistry.     (Orndorff.)  ..  ..Svo,  2  50 

*  Satterlee's  Outlines  of  Human  Embryology 12mo,  1   25 

Smith's  Lecture  Notes  on  Chemistry  for  Dental  Students Svo,  2  50 

*  Whipple's  Tyhpoid  Fever Large  12mo,  3  00 

*  Woodhull's  Military  Hygiene  for  Officers  of  the  Line Large  12mo,  1   50 

*  Personal  Hygiene 12mo,  1  00 

Worcester  and  Atkinson's  Small  Hospitals  Establishment  and  Maintenance, 

and  Suggestions  for  Hospital  Architecture,  with  Plans  for  a  Small 

Hospital 12mo,  1  25 

METALLURGY. 

Betts's  Lead  Refining  by  Electrolysis Svo.  4  00 

Bolland's  Encyclopedia  of  Founding  and  Dictionary  of  Foundry  Terms  used 

in  the  Practice  of  Moulding 12mo.  3  00 

16 


Iron  Founder 12mo,  $2  50 

Supplement 12mo,  2  50 

*  Borchers's  Metallurgy.      (Hall  and  Hayward.) 8vo,  3  00 

Burgess   and   Le   Chatelier's   Measurement  of   High   Temperatures.     Third 

Edition.      (In  Press.) 

Douglas's  Untechnical  Addresses  on  Technical  Subjects 12mo,  1   00 

Goesel's  Minerals  and  Metals:  A  Reference  Book 16mo,  mor.  3  00 

*  Iles's  Lead-smelting 12mo,  2  50 

Johnson's    Rapid    Methods   for    the   Chemical    Analysis    of    Speci&l   Steels, 

Steel-making  Alloys  and  Graphite Large  12mo,  3  00 

Keep's  Cast  Iron 8vo,  2  50 

M-stcalf 's  Steel.      A  Manual  for  Steel-users 12mo,  2  00 

Minet's  Production  of  Aluminum  and  its  Industrial  Use.      (Waldo.).  .  12mo,  2  50 
Palmer's  Foundry  Practice.      (In  Press.) 

*  Price  and  Meade's  Technical  Analysis  of  Brass 12mo,  2  00 

*  Ruer's  Elements  of  Metallography.      (Mathewson.) .  .  .  .' 8vo,  3  00 

Smith's  Materials  of  Machines 12mo,  1   00 

Tate  and  Stone's  Foundry  Practice 12mo,  2  00 

Thurston's  Materials  of  Engineering.      In  Three  Parts 8vo,  8  00 

Part  I.       Non-metallic  Materials  of  Engineering,  see  Civil  Engineering, 
page  9. 

Part  II.    Iron  and  Steel 8vo,  3  50 

Part  III.  A  Treatise  on  Brasses,   Bronzes,  and  Other  Alloys  and  their 

Constituents 8vo,  2  50 

Ulke's  Modern  Electrolytic  Copper  Refining 8vo,  3  00 

West's  American  Foundry  Practice 12mo,  2  50 

Moulders'  Text  Book 12mo.  2  50 


MINERALOGY. 

Baskerville's  Chemical  Elements.      (In  Preparation.) 

*  Browning's  Introduction  to  the  Rarer  Elements 8vo, 

Brush's  Manual  of  Determinative  Mineralogy.      (Penfield.) 8vo, 

Butler's  Pocket  Hand-book  of  Minerals 16mo,  mor. 

Chester's  Catalogue  of  Minerals 8vo,  paper, 

Cloth, 

*  Crane's"Gold  and  Silver 8vo, 

Dana's  First  Appendix  to  Dana's  New  "System  of  Mineralogy".  .Large  8vo, 
Dana's  Second  Appendix  to  Dana's  New  "  System  of  Mineralogy." 

Large  8vo, 

Manual  of  Mineralogy  and  Petrography 12mo, 

Minerals  and  How  to  Study  Them 12mo, 

System  of  Mineralogy Large  8vo,   half  leather. 

Text-book  of  Mineralogy 8vo, 

Douglas's  Untechnical  Addresses  on  Technical  Subjects 12mo, 

Eakle's  Mineral  Tables 8vo, 

Eckel's  Building  Stones  and  Clays.      (In  Press.) 

Goesel's  Minerals  and  Metals:  A  Reference  Book 16mo,  mor. 

*  Groth's  The  Optical  Properties  of  Crystals.      (Jackson.) 8vo, 

Groth's  Introduction  to  Chemical  Crystallography  (Marshall) 12mo, 

*  Hayes's  Handbook  for  Field  Geologists 16mo,  mor. 

Iddings's  Igneous  Rocks 8vo, 

Rock  Minerals 8vo, 

Johannsen's  Determination  of  Rock-forming  Minerals  in  Thin  Sections.  8vo, 

With  Thumb  Index 

*  Martin's  Laboratory     Guide    to    Qualitative    Analysis    with    the    Blow- 

pipe  c 12mo, 

Merrill's  Non-metallic  Minerals:  Their  Occurrence  and  Uses 8vo, 

Stones  for  Building  and  Decoration 8vo, 

*  Penfield's  Notes  on  Determinative  Mineralogy  and  Record  of  Mineral  Tests. 

Svo,  paper. 

Tables  of   Minerals,    Including  the  Use  of   Minerals  and   Statistics  of 

Domestic  Production 8vo, 

*  Pirsson's  Rocks  and  Rock  Minerals 12mo, 

*  Richards's  Synopsis  of  Mineral  Characters 12mo,  mor. 

*  Ries's  Clays:  Their  Occurrence,  Properties  and  Uses Svo, 

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*  Ries  and  Leighton's  History  of  the  Clay-working  mnustry  of  the  United 

States 8vo,  $2  50 

*  Rowe's  Practical  Mineralogy  Simplified 12mo,  1   25 

*  Tillman's  Text-book  of  Important  Minerals  and  Rocks 8vo,  2  00 

Washington's  Manual  of  the  Chemical  Analysis  of  Rocks 8vo,  2  00 

MINING. 

*  Beard's  Mine  Gases  and  Explosions Large  12mo,     3  00 

*  Crane's  Gold  and  Silver 8vo,     5  00 

*  Index  of  Mining  Engineering  Literature 8vo,     4  00 

-  *  8vo,  mor.  5  00 

*  Ore  Mining  Methods. • 8vo,  3  00 

*  Dana  and  Saunders's  Rock  Drilling _ Svo,  4  00 

Douglas's  Untechnical  Addresses  on  Technical  Subjects ! 12mo,  1   00 

Eissler's  Modern  High  Explosives Svo,  4  GO 

Goesel's  Minerals  and  Metals:  A  Reference  Book 16mo,  mor.  3  00 

Ihlseng's  Manual  of  Mining Svo,  5  00 

*  Iles's  Lead  Smelting 12mo,  2  50 

*  Peele's  Compressed  Air  Plant Svo,  3  50 

Riemer's  Shaft  Sinking  Under  Difficult  Conditions.      (Corning  and  PeeIe.)8vo,  3  00 

*  Weaver's  Military  Explosives Svo,  3  00 

Wilson's  Hydraulic  and  Placer  Mining.      2d  edition,  rewritten 12mo,  2  50 

Treatise  on  Practical  and  Theoretical  Mine  Ventilation 12mo,      1  25 

SANITARY    SCIENCE. 

Association  of  State  and  National  Food  and  Dairy  Departments,  Hartford 

Meeting,  1906 Svo, 

Jamestown  Meeting,  1907 Svo, 

*  Bashore's  Outlines  of  Practical  Sanitation 12mo, 

Sanitation  of  a  Country  House 12mo, 

Sanitation  of  Recreation  Camps  and  Parks 12mo, 

*  Chapin's  The  Sources  and  Modes  of  Infection Large  12mo, 

Folwell's  Sewerage.      (Designing,  Construction,  and  Maintenance.) Svo, 

Water-supply  Engineering Svo, 

Fowler's  Sewage  Works  Analyses 12mo, 

Fuertes's  Water-filtration  Works 12mo, 

Water  and  Public  Health 12mo, 

Gerhard's  Guide  to  Sanitary  Inspections 12mo, 

*  Modern  Baths  and  Bath  Houses Svo, 

Sanitation  of  Public  Buildings 12mo, 

,*  The  Water  Supply,  Sewerage,  and  Plumbing  of  Modern  City  Buildings. 

Svo, 

Hazen's  Clean  Water  and  How  to  Get  It Large  12mo, 

Filtration  of  Public  Water-supplies Svo, 

*  Kinnicutt,  Winslow  and  Pratt's  Sewage  Disposal Svo, 

Leach's  Inspection  and  Analysis  of  Food  with  Special  Reference  to  State 

Control Svo, 

Mason's  Examination  of  Water.      (Chemical  and  Bacteriological) 12mo, 

Water-supply.      (Considered  principally  from  a  Sanitary  Standpoint). 

Svo, 

*  Mast's  Light  and  the  Behavior  of  Organisms Large  12mo, 

*  Merriman's  Elements  of  Sanitary  Engineering Svo, 

Ogden's  Sewer  Construction Svo, 

Sewer  Design 12mo, 

Parsons's  Disposal  of  Municipal  Refuse Svo, 

Prescott  and  Winslow's  Elements  of  Water  Bacteriology,  with  Special  Refer- 
ence to  Sanitary  Water  Analysis 12mo, 

*  Price's  Handbook  on  Sanitation 12mo, 

Richards's  Conservation  by  Sanitation Svo, 

Cost  of  Cleanness -. 12mo, 

Cost  of  Food.      A  Study  in  Dietaries 12mo, 

Cost  of  Living  as  Modified  by  Sanitary  Science 12mo, 

Cost  of  Shelter 12mo, 

*  Richards  and  Williams's  Dietary  Computer Svo, 

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Richards  and  Woodman's  Air.  Water,  and  Food  from  a  Sanitary  Stand- 

*  ^.  ,       .P^'^i^V  ••.•••;••;. 8vo.  $2  OG 

*Richeys     Plumbers.     Steam-fitters',    and     Tinners'     Edition     (Building 

Mechanics'  Ready  Reference  Series) 16mo,  mor. 

Rideal's  Disinfection  and  the  Preservation  of  Food '.','. .'.8vo. 

Soper's  Air  and  Ventilation  of  Subways '  '  .',*.*.'.'.*.'.'.'.*.*  '  '  *  I'^mo' 

Tumeaure  and  Russell's  Public  Water-supplies '.'.'.*.*.'.*.".*.*.*.'.'.'.  .~8vo' 

Venable's  Garbage  Crematories  in  America isvo,' 

Method  and  Devices  for  Bacterial  Treatment  of  Sewage 8vo! 

Ward  and  Whipple's  Freshwater  Biology.      (In  Press.) 

Whipple's  Microscopy  of  Drinking-water gvo, 

*  Typhoid  Fever.  .  .  , .".'.*.".'.*.".* .Large  V2mo! 

Value  of  Pure  Water Large  12mo. 

Winslow's  Systematic  Relationship  of  the  Coccaceje Large  12mo, 

MISCELLANEOUS. 

*  Burt's  Railway  Station  Service 12mo, 

*  Chapin's  How  to  Enamel '  '  ' '  '    12mo' 

Emmons's  Geological  Guide-book  of  the  Rocky  Mountain  Excursicn  of"  the 

International  Congress  of  Geologists Large  8vo, 

Ferrel's  Popular  Treatise  on  the  Winds "..,'...  .Svo' 

Fitzgerald's  Boston  Machinist '.V.Vsmo' 

*  Fritz,  Autobiography  of  John gyo' 

Gannett's  Statistical  Abstract  of  the  World '.',  .  .'..*.".'. '.V24mo' 

Haines's  American  Railway  Management 12mo,' 

Hanausek's  The  Microscopy  of  Technical  Products.      (Win ton) 8vo,' 

Jacobs's  Betterment    Briefs.      A    Collection    of    Published    Papers    on    Or- 
ganized Industrial  Efficiency gvo, 

Metcalfe's  Cost  of  Manufactures,  and  the  Administration  of  Workshops.. Svoi 

Putnam's  Nautical  Charts 8vo, 

Ricketts's  History  of  Rensselaer  Polytechnic  Institute  1824-1894. 

Large  12mo, 

*  Rotch  and  Palmer's  Charts  of  the  Atmosphere  for  Aeronauts  and  Aviators. 

Oblong  4to, 

Rotherham's  Emphasised  New  Testament Large  8vo, 

Rust's  Ex-Meridian  Altitude,  Azimuth  and  Star-finding  Tables 8vo 

Standage's  Decoration  of  Wood,  Glass,  Metal,  etc , 12mo 

Thome's  Structural  and  Physiological  Botany.      (Bennett) 16mo. 

Westermaier's  Compendium  of  General  Botany.      (Schneider) Svo. 

Winslow's  Elements  of  Applied  Microscopy 12mo, 

HEBREW   AND    CHALDEE    TEXT-BOOKS. 

Gesenius's  Hebrew  and  Chaldee  Lexicon  to  the  Old  Testament  Scriptures. 

(Tregelles.) Small  4to.  half  mor,     5  00 

Green's  Elementary  Hebrew  Grammar 12mo.     1  25 


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UNIVERSITY  OF  CALIFORNIA  LIBRARY 

Los  Angeles 
This  book  is  DUE  on  the  last  date  stamped  below. 


APR  2  2  19B4 


DEC  10  1985 
DEC     1  RCB 


Form  L9-42m-8,'49(B5573)444 


